DF Flashcards
(425 cards)
1
Q
Why formulate drugs?
A
- Facilitate manufacturing
- Reproducible quality
- eg lubricants
- For stability
- Protect from light, heat, moisture, pH etc
- During manufacture, storage & after administration
2
Q
Why formulate drugs cont..
A
- Enable handling by the patient
- Functional - to improve bioavailability
- eg enteric coating
3
Q
Which route of administration?
A
- Parenteral
- Oral
- Pulmonary
- Transdermal
- Rectal
- Ocular
- Nasal
4
Q
Mechanism of drug release:
L1, pg 16
A
kjhgfdg
5
Q
Example: Diclofenac
L1, pg 17
A
kjhgfds
6
Q
Dissolution
Dissolution =?
Key point:
Noyes-Whitney equation:
L1, pg 18
A
Dissolution
Dissolution = drug particles dissolve
Key point: Drug must be in solution to be absorbed
Noyes-Whitney equation:
- dm/dt = kA(Cs-C)
7
Q
Increasing surface area for distribution:
L1, pg 19
A
- Intact tablet = low rate of dissolution
- Granules = moderate rate of dissolution
- Primary drug particles = relatively rapid rate of dissolution
8
Q
Oral administration
L1, pg 20
A
- Release from dosage form into solution ie dissolution (Solubility)
- Drug absorption (Permeability)
9
Q
An amorphous (or non-crystalline solid/glass) is a:
A
Solid that lacks the long-range order that is the characteristic of a crystal
10
Q
In a crystal, the atoms or molecules are arranged in a:
A
- regular, periodic manner.
11
Q
Crystalline solids:
term that describes a:
L2, pg 6
A
Solid of regular shape and the presence of three-dimensional order on the level of atomic dimension, for a given. molecule
12
Q
Amorphous solids
L2, pg 7
A
- Solid substances that are not crystals
- Amorphous solids consist of randomly oriented molecules
- Solids w/out definite shape consist of randomly oriented molecules
- No regular 3D arrangement
13
Q
Amorphous & crystalline solids
L2, pg 8
A
Crystalline solids
- Definite shape and geometrical form
- Sharm melting point
- Clean cleavage, ie, break into pieces w/ plane surfaces
- Anistrophic (mechanical & electrical properties depend on the direction along which they are measured)
Amorphous solids
- No definite geometrical shape
- Melt over wide range of temperatures
- Give irregular cleavage
- Isotrophic (similar physical properties in all directions because the constituents are arranged in random manner)
14
Q
Random shit L2, pg 9 & 10 & 11 & 12 & 13
A
Equilibrium solubility of amorphous and crystalline Atorvastatin
- Solubility decreased to 200ug/ml after 24hr due to amorphous to crystalline transition
15
Q
Amorphous & crystalline solids - Assuming particle size the same:
Stability:
Solubility:
Dissolution rate:
…. & … of amorphous will be faster than stable … form
A
Stability: AMORPHOUS < STABLE CRYSTAL
Solubility: AMORPHOUS > STABLE CRYSTAL
Dissolution rate: AMORPHOUS > STABLE CRYSTAL
ABSORPTION & ACTIVITY of amorphous will be faster than stable … form
16
Q
Altered activity: Aluminium hydroxide gel
L2, pg 15
A
Aluminium hydroxide gel amorphous form»_space;> good acid neutralization properties
- Upon aging, it crystallizes»_space;> little acid reactivity
17
Q
Advantages & Disadvantages of using amorphous form of a drug in a tablet
A
Advantages
- Increased solubility
- Increased dissolution rate of particles
- Increased bioavailability - rate & extent of absorption
Disadvantages
- Amorphous - unstable - can crystallise out,, thus reducing solubility, dissolution & bioavailability
- Increase in particle size during crystallisation or during change in crystal form w/ reduction in surface area & dissolution
18
Q
Glass transition temperature
Glass transition temperature is the temperature at which amorphous materials change from?
L2, pg 17
A
- A relatively brittle “glassy” state into a viscous or rubbery state
19
Q
Formulation strategies that might be used to stabilise amorphous drugs:
L2, pg 18
A
- POLYMER TO INCREASE Tg so that the amorphous drug remains in the glassy state where the molecular mobility is less
- POLYMER THAT HAS INTERACTIONS with the amorphous drug; if the amorphous interacts w/ the polymer it is less likely to form nuclei & crystallise
20
Q
Outline desirable storage conditions for amorphous and crystalline drugs
A
- Amorphous solids are more unstable in the presence of moisture - likely due to the reduction in Tg so that molecular mobility increases, leading to the formation of nuclei & crystallisation
- Protect from MOISTURE & HIGH TEMPERATURE
21
Q
What is bioavailability?
L1, pg 24
A
- Fraction of administered dose that reaches systemic circulation intact
22
Q
Bioequivalence definition:
L1, pg 25 & 27
A
The absence of a significant difference in the rate and extent to which the active ingredient becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study
23
Q
Difference b/w generic & innovator medicines
L1, pg 26 & 27 & 28
A
Innovator medicine
- Brand/trade/proprietary
- Patent protected
Generic medicine
- Multi-source
- Not patent protected
- Same API, route administration, same indication, same strength, same dosage form
24
Q
What is a solution?
- Solution =?
A
- Chemically & physically homogenous mixture of two or more substances
- Solution = Solute & solvent
25
Saturated vs unsaturated solutions
L5, pg 33
Saturated
- Solution = the solubility of the solute
Unsaturated
- solution
26
Solvents in solution:
L5, pg 34
Solvents in solution
Choosing a solvent (vehicle)
- Application requirements (where and for who?)
- Solubility
- Toxicity & or irritancy
- Stability
- Cost
- Aqueous vs oily
- Water
- Potable water
- Purified BP
- Water for injection BP
- Co-solvents often required
27
Pharmaceutical solutions =?
Solute + solvent + excipients
28
Classification of pharmaceutical solutions:
- According to the route of administration
- According to composition and uses
- According to the vehicle
29
Classification: route of administration:
- Oral solution
- Ophthalmic solution
- Nasal solutions
- Intravenous solutions
- Topical solution
30
Classification: solvent (vehicle)
* Aqueous solutions:
* Non-aqueous (oily) solution:
Classification: solvent (vehicle)
* Aqueous solutions:
- Solutions that contain water as the solvent
* Non-aqueous (oily) solution:
- Solutions that contain a solvent other than water eg alcohols or oils
31
Classification: composition and uses
Syrups:
Elixer:
Classification: composition and uses
Syrups:
- Are concentrated aqueous solutions that contain alcohol (<10%) for oral use
Elixer:
- Are clear hydroalcoholic (combination of water & ethanol solution) for oral use
32
What's a good pharmaceutical solution?
- Stability
- Palatable (acceptance to patients)
- Sterility
- Compatible w/ physiological fluids
- Irritancy
33
Exipients (some common examples)
- Preservatives
- Sweereners & or flavours and colours
- Antioxidants
- Buffer
- Rheology (viscosity( modifiers
34
Preservatives
* Prevent:
* Not usually required if:
* Desirable properties
* Often mixtures of preservatives are used:
Preservatives
* Prevent:
- Microbial contamination
* Not usually required if:
- single-use product
* Desirable properties:
- Non-toxic, non-sensitising, odourless, tasteless
- Effective in low conc. and against a variety of microorganisms
- Compatible w/ other components
- Long-term stability
* Often mixtures of preservatives are used:
- Increase spectrum of antimicrobial activity
- Synergistic effec -> dec. conc.
- Dec. toxicity
- Dec. emergence of resistant micro-organisms
35
Examples of preservative - dont need to know this but maybe get a broad overview
- L5, pg 43& 44 & 45
defsrgt
36
What is particle size of a drug?
L6, pg 7
Volume of particle = volume of equivalent sphere
37
What is milling?
- Milling is a unit operation where high energy is applied to break down coarse particles into fine particles
- Dry milling & wet milling
38
Particle size & surface area:
L6, pg9
As particle size decreases, surface area increases
39
Influence of particle size on dissolution and activity:
- Higher surface area allows intimate contact of the drug with the dissolution fluids in vivo & increases the drug solubility & dissolution
- Higher the dissolution, faster the absorption & hence quicker & greater the drug action
40
Influence of particle size on surface area & dissolution
- Just have a look at the particle size influence
L6, pg 11
Smaller the particle, larger the surface area
41
Problems during or following dry milling
- Amorphous drug may be produced (not always desired)
- Changed to another polymorphic form may occur
- Heat production may occur
- Degradation due to heat build-up may occur
- Hygroscopic substances absorb moisture
- Static build-up may occur
42
Moisture content definition:
relative humidity (RH) definition:
Moisture content definition:
- The MASS of moisture present in a sample. It is the LOSS IN WEIGHT (%) AFTER OVEN DRYING 102*C until CONSTANT WEIGHT is obtained
- %MOISTURE CONTENT = (initial weight - dry weight)
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relative humidity (RH) definition:
- Is the saturation level of the air with water vapour-normally expressed as a percentage. A higher percentage means that the air-water mixture is more humid. At 100% RH, the air is saturated. RH depends on moisture content and temperature
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43
Pharmaceutical examples where good mixing is important:
L6, pg 15
- CORRECT AMOUNT OF EACH EXCIPIENT in each dose is important as the excipient can influence the release characteristics & therefore the plasma level profiles of the product
- CORRECT COMPOSITION is important to promote a physical or chemical interaction, such as for tabletting or dissolution
44
Theory of powder mixing:
L6, pg 16
- Types of mixes
- A perfect powder mix would be one in which the various components were distributed in a uniform manner throughout the system, as in a solution of a drug. But, in practice, we achieve a random mix
45
Challenges to mixing
- He kinda zoomed over this
L6, pg 17
- When the drug content is only small proportion of the mix
- When the drug particles (or other ingredients) are aggregated or agglomerated initially; not easy to separate to achieve a good random mix (need for blending procedure)
- When the mixing procedure
46
Demixing (segregation) definition:
- Can occur at the same time as mixing occurs. segregation may occur when one component concentrates at one position in the mixer, especially where symmetric repetitive movement occurs
- Can occur when the external mixing procedure stops
47
Factors promoting segregation
- Differences in particle size, shape & density
- Size or density means gravity can lead to segregation
- Asymmetric movement or abrupt reversal in movement helps to reduce this
48
Like dissolves like
L7, pg 51 & 52
regtr
49
Nature of solute governs solubility
* Chemical structure (intermolecular forces):
* Solid state structure
Nature of solute governs solubility
* Chemical structure (intermolecular forces):
- Ability to form hydrogen bonds
- Effect of substituents (ratio of the polar to non-polar groups or hydrophobic nature of the solute)
- Charge strength
- Degree of ionisation of functional groups
* Solid state structure
50
Ability to form hydrogen bonds
- eg neutral molecules
L7, pg 54 & 55
- Ethanol can hydrogen bond with water
| - Many O-H bonds for hydrogen bonding to H2O
51
hydrophobic nature of the solute
Have a wee look at the trend
- L7, pg 56 & 57 & 58 & 59
- Mant nonpolar C-C and C-H bonds
| - Most of the molecule is nonpolar, so it is not attracted to a polar solvent like H2O
52
Ionic molecules & charge strength
*ionic bonds differ in strength - water cant break some bonds:
- Molecules w/ small charges: higher solubility
- eg NaOH - Na+ and OH-
Molecules with large charges: lower solubility
- eg Ca(OH)2. - Ca2+ and 2(OH)-
53
Solubility of ionic compounds : general rules
L7, pg 61
Cation & anion in the ionic compound can be used to predict its aqueous solubility
- A compound is soluble if it contains one of the following cations: Li+, Na+, K+, Ammonium, NH4+
- A compound is soluble if it contains one of the following anioins
- Halide: Cl-, Br-, I-
- Nitrate, NO3-
- Acetate, Ch3CO2-
- Sulfate, SO42-
54
Degree of ionisation: strong electrolytes
L7, pg 62
NaCl ---> Na+ + Cl-
- Electrolytes (must contain ions)
- Ionic compounds (NaCl)
- Strong acids and bases (HCl & NaOH)
55
Degree of ionisation: weak electrolytes
L7, pg 63
- eg acetylsalicylic acid (aspirin)
- Weak electrolytes
- Weak acids and bases
56
%ionised: weak acids
- L7, pg 64 & 65
Ionisation of weak electrolytes is dependent on solution
- % = 100/ 1 + 10(pka-pH)
- Weak acids are more soluble in a base
57
% ionised: weak base
- L7, pg 66 & 67 & 68
- %ionised = 100 / 1 + 10 (ph-pka)
| - Weak bases are more soluble in an acid
58
Nature of solvent
* Chemical structure
- Polarity (dipole moment)
- Ability to form hydrogen bonds
* pH (if solute or drug is a weak electrolyte)
59
Polarity and dielectric constant
* have a wee look on L7, pg 70
- Dielectric constant: predictor (rough measure') of polarity (determined by ability to conduct an electric current)
60
Polar solvents:
- High dielectric constant (water)
- Readily dissolve ionic compounds because they are capable of ion-dipole interaction
- Dec. interionic attractions in ionic crystals, and in general dissolve polar solutes eg strong electrolytes
61
Non-polar solvents:
- Low dielectric constant
- Do not greatly reduce interionic attractions in ionic crystals therefore will not dissolve polar solutes
- Non-polar solvents dissolve non-polar solutes through induced dipole interactions
62
Semi-polar solvents:
- Act as intermediate solvents to inc. solubility
| - Induce a degree of polarity in non-polar molecules
63
Strategies to improve solubility of weak electrolytes:
Physical modification
- Solid state/crystalline
Chemical Modifications
1) Salt formation
2) Co-solvents
3) pH adjustment (buffers)
4) Complexation
64
Salt formation:
- L8, pg 78 + 79 + 80
Salt formation:
| - Salts of organic (weak) acids & bases are usually very soluble in water
65
Co-solvency:
L8, pg 81 + 82 (graph) + 83 (graph) + 84 (Solubility of weak electrolytes in co-solvents) + 85 (selecting suitable co-solvents)
* Phenomenon where a solute is more soluble in a mixture of solvents than in one solvent alone
* Common pharmaceutical co-solvents (semi-polar)
- ethanol
- propylene glycol
- Glycerol
* Often a combination of co-solvents are used
* Important in formulation of injectable solutions
66
Solubility of weak electrolytes in co-solvents:
* Co-solvents adjusting solvent polarity
- dec. water-water interaction
- Some degree of H-bonding
- Induce dipole interaction
- --> Inc. solubility of unionised species
* Can also influence pKa, therefore pH adjustment is often required
67
pH adjustment:
L8, pg 86
pH adjustment:
* Most drugs are weak acids or bases (weak electrolytes)
* Alterations in pH -> ionisation of drug -> aqueous solubility
68
pH adjustment:
How can we predict changes in solubility brought about by alterations of solvent pH?
L8, pg 86 + 87 + 88
- Dont need to memorise equation - need to know how to apply
* Predicted by the pHp equation
| - pHp is the pH below which acid or above which base will begin to precipitate
69
Calculating solubility: Practice examples
L8, pg 89 + 90 +91 + 92 + 93 +94
,mnbvc
70
Types of tablets
L9, pg 7
A) Tablets ingested orally
1. Compressed tablet
2. Multiple compressed tablet
3. Delayed release tablet
4. Sugar coated tablet
5. Film coated tablet
6. Chewable tablet
B) Tablets used in oral cavity
1. Buccal tablet
2. Sublingual tablet
3. Lozenges
C) Tablet administered by other routes
1. Implantation tablet
2. Vaginal tablet
D) Tablets used to prepare solution
1. Effervescent tablet
71
Plain/ conventional/ compressed oral tablets:
L9, pg 8
Oral tablets
72
Multiple compressed tablets/ layered tablets:
Have:
Control:
Multiple compressed tablets/ layered tablets:
Have:
- Have two or more layers of ingredients
Control:
- Control release of the formulation
73
Delayed release tablets
The equate delayed release tablet is used for:
Not intended for:
Delayed release tablets
The equate delayed release tablet is used for:
- Treating frequent heartburn that occurs two or more days a week
Not intended for:
- Immediate relief of heartburn, as it may take 1 to 4 days for full effect
74
Coated tablets:
Coated tablets:
* Film coated tablet
- eg, levetiracetam tablet
75
Sugar coated tablet:
L9, pg 13
Sugar coated tablet:
| - Tofranil tablet
76
Chewable tablets:
Chewable tablets:
- Always very big - 1.5 g
- Deliberate to stop people swallowing the tablets whole
- Mechanically disintegrated in the mouth - no disintegrant
- CONTAIN SORBITOL OR MANNITOL AS FILLERS
- The drug is not dissolved in the mouth but swallowed and dissolved in the intestine. eg antacids
- Mylanta: aluminium oxide, magnesium oxide
77
Buccal tablets:
- Where are buccal tablets placed?
- How do these drugs avoid first pass metabolism?
- Buccastem:
Buccal tablets:
- Buccal tablets are placed in the side of the cheek
- Drugs are dissolve, rapidly absorbed to give rapid systemic action avoiding first pass metabolism
- Buccastem: Prochlorperazine, compressible sugar, povidone K30, xanthan gum, locust bean gum, talc, magnesium stearate & riboflavin sodium phosphate
78
Sublingual tablets:
- Where are these tablets placed?
- How do these drugs avoid first pass metabolism?
- Eg:
Sublingual tablets:
- Sublingual tablets are placed under the tongue
- Drugs are dissolved, rapidly absorbed to give rapid systemic action avoiding first pass metabolism
- Eg, glyceryl trinitrate
79
Compressed lozenges:
- Where does the drug dissolve?
- Mycostatin:
Compressed lozenges:
- Dissolve drug in the mouth for systemic uptake or for local medication in the mouth or throat, eg, w/ local anaesthesia, antiseptic & antibiotic
- Mycostatin: CORE - nystatin, lactose, corn starch, talc, magnesium stearate
80
Implants (jadelle)
Where?
How is the drug released?
No need for? Can cause?
What are given in implants?
Implants (jadelle)
- Put in the body sub-surfaces mostly below the skin or into muscles
- Release the drug slowly over a period of months to year
- No need for regular administration of the drug if these implants are used. But they can cause pain and sometimes release excess drug leading to toxicity
- Contraceptives, steroids are given in implants
81
Vaginal tablet/pessaries:
- Canesten Clotrimazole once
Pessary contains clotrimazole 500 mg
Do not take by mouth
- It contains one pessary which is a tablet inserted high into the vagina to get right to source of the infection. If you suffer from repeated infections a longer treatment is advised
82
Effervescent tablets:
Effervescent tablets:
- Very big to prevent swallowing
- Carbon dioxide is produced by a reaction in water b/w a carbonate or bicarbonate and a weak acid such as citric or tartaric
- Contain water soluble lubricant and no binder
- Good for rapid release - already in solution. Quick action - eg aspirin
83
Polymorphs definition:
(True) polymorphs:
- Solid material that exists at least in two different molecular arrangements, ie, distinctly different crystal species
- Different 3D arrangements in the crystal lattices
- Often different melting points; aqueous solubilities & dissolution rates
84
Polymorphs: Carbamazepine (CBZ)
L3, pg 7
- Carbamazepine (CBZ) has 4 polymorphs (forms I, II, II, IV) one 3D arrangement will be most stable; the others are metastable ie these metastable forms could change to a more stable form - perhaps with increase in temperature or contact with moisture
85
Stable & Metastable polymorphs (crystal forms):
L3, pg 8
- Metastable polymorphs have higher energy than the stable polymorph
86
Relationship b/w the various polymorphic forms
Assuming the particle size the same:
- Stability: metastable crystal < stable crystal
- Solubility: Metastable > stable
- Dissolution rate: Metastable > stable
87
Relationship b/w the various solid state forms
Assuming particle size the same:
- Stability: amorphous < metastable crystal < stable crystal
- Solubility: Amorphous > metastable > stable
- Dissolution rate: Amorphous > Metastable > Stable
88
Different solubilities of polymorphs: Riboflavine
- L3, pg 11
- A metastable form may have higher solubility (KINETIC OR METASTABLE SOLUBILITY) than the most stable form (EQUILIBRIUM SOLUBILITY)
89
Pharmaceutical implications of polymorphs
Chloramphenicol palmitate: Form A & Form B
L3, pg 12
Form B metastable form;
- Higher solubility & bioavailability
Form A Stable form;
- Low solubility & bioavailability
90
Formulation challenges of solution of metastable polymorphs:
L3, pg 13 + 14 + 15
- If a 'saturated' solution is prepared using a metastable polymorph of a drug, the polymorph can change to its stable polymorph during storage. Therefore, the solubility of the drug will decrease. As a result, excess drug will be crystallized
91
Advantages & disadvantages of using a metastable polymorph IN A SUPENSION
Advantages
- Inc. conc. in solution (inc. solubility)
- Inc. dissolution rate of suspended particles
- Inc. bioavailability - rate and extent of absorption
Disadvantages
- Change to stable crystal form
- Reduction in concentration in solution to equilibrium solubility
- Sometimes crystals may get bigger, reducing surface area
- Reduction in dissolution rate of suspended particles
- Reduction in bioavailability
92
Advantages & disadvantages of using a metastable polymorph IN A TABLET
Advantages
- Inc. solubility
- Inc. dissolution rate of particles
- Inc. bioavailability - rate & extent of absorption
Disadvantages
- METASTABLE TO STABLE; reduced solubility, dissolution & bioavailability
93
Formulation strategies of metastable polymorphs in suspension:
L3, pg 18 - not in assessable tasks - but maybe have a read
If seed crystals of the more stable (and less soluble) polymorph are added, polymorph transformation is faster; the solid state transformation may be slowed down or prevented by adding protective colloids
94
Storage & formulation strategies for tablets containing metastable polymorph:
- Protection from moisture & storage at temperatures at usual room temperature (RT) or less would be beneficial
- Inhibitory polymers could be included in the tablet formulation
95
Solvates, Co-crystals & salts
L3, pg 20
Cocrystals (multi-component crystals) two or more components within the same crystal lattice
Co-crystal (or cocrystal) - API w/ another substance (another API or other substance) often leading to increase in solubility, dissolution rate & bioavailability
96
Pseudo (false) polymorphs
L3, pg 21
Solvates - with water, ethanol, acetone etc
| eg theophylline monohydrate (less soluble than anhydrate; may form during dissolution of anhydrate)
97
Conversion from anhydrous to hydrate: eg THEOPHYLLINE
- Hydrate crystals may form from a solution of anhydrous theophylline
98
Prerequisites of the particulate system
L10, pg 6
Step 1: Particulate ingredients are fed into a die
Prerequisite 1: Particles must be free flowing
Step 2: Particulates are compressed b/w punches
Prerequisite 2: Particles must cohere on compression
Step 3: Compacted mass is ejected from the die
Prerequisite 3: Tablet must not adhere to punches of die and must remain coherent after ejection
99
Excipients: Diluents (bulking agents/ fillers)
Function:
Examples:
L10, pg 7 + 8
Excipients: Diluents (bulking agents/fillers)
- Microcrystalline cellulose
- Calcium hydrogen phosephate dihydrate
- Sugars such as glucose, sucrose, sorbitol & mannitol are primarily used in lozenges or chewable tablets
Mannitol has a negative heat or solution and imparts a cooling sensation when sucked or chewed
Excipients: Diluents (bulking agents/ fillers)
Function: To form a tablet suitable for handling (<50 mg)
Examples:
- Lactose is the most common
- Maillard reaction w/ primary & secondary amines
100
Excipients: Binders (adhesives)
Function:
Types:
L10 , pg 9 & 10
BINDERS for the wet granulation process
Synthetic polymers
- polyvinyl pyrrolidone (PVP), granulating of water sensitive drug
- Polyvinyl acetate (PVAC) (poorly soluble in water), results in prolonged disintegration time
Semisynthetic polymers
- Methylcellulose (MC), Hydroxyethyl cellulose (HEC), Hydroxypropyl cellulose (HPC)
- Carboxymethyl cellulsoe (CMC)
- CMC is anionic: incompatibilities possible with cationic substances
Excipients: Binders (adhesives)
Function:
- Bind powder particles together in granules
- Bind granules in tablet (during compression)
Types:
- Dry binder: cellulose, methyl cellulose, POLYVINYL PYRROLIDONE and polyethylene glycol
- Solution binder: gelatin, polyvinyl pyyrolidone, cellulose derivatives (HPMC), polyethylene glycol, starch &sucrose
101
Excipients: Disintegrants
Function:
Types:
L10, pg 11 + 12
iii) Swell upon contact w/ water
- Traditional disintegrants
- Starch (including pregelatinised) (10%)
- Alginic acid, alginates
- Superdisintegrants
- Sodium starch glycolate (4%)
- Cross povidone (cross-linked polyvinyl pyrrolidone, PVP)
- Cross-carmellose sodium (cross-linked sodium carboxymethylcellulose, NaCMC (2-5%)
Disintegrants are not included in chewable tablets
Excipients: Disintegrants
Function:
- Facilitate break up into small fragments in presence of liquid, which increases surface area and promotes rapid drug dissolution
Types:
(i) - facilitate water uptake & transport liquids into the pores of the tablet eg surface active agents
- or, increase the penetration rate of water into the tablet
- eg wetting agents
- Examples: sodium dodecyl sulphate (SDS)
(ii) - produce gas in contact w/ moisture
- Mixtures of tartaric acid or citric acid and sodium bicarbonate or calcium carbonate: gas produced is (CO2)
102
Excipients: Glidants (anti-caking agents)
L10, pg 13
Function
- used in formulation to improve the flowability of the powder mixture by reducing interparticulate friction
Examples
- Colloidal silica is most commonly used
- traditionally talc
- Magnesium stearate
103
Excipients: lubricants
L10, pg 14 + 15
Lack of lubricants in formulation results in high friction which may lead to capping or fragmentation of tablets during ejection and vertical scratches on tablet edge
Excessive lubricants may lead to
- Poor tensile strength
- Retarded tablet disintegration and dissolution (more due to hydrophobic nature of lubricants)
Function
- Facilitate ejection of the tablet by reducing friction b/w tablet and die
examples
- Magnesium stearate (most common), stearic acid, polyethylene glycol, sodium lauryl sulphate, sodium stearyl fumarate
104
Excipients: Antiadherants
L10, pg 16
Problems
- Lack of antiadherant will result in build up of a thin layer of pwder on punches, which in turn will lead to an uneven and matt tablet surface with unclear markings and symbols
Function
- Reduce adhesion b/w powder and the surface of punches to prevent particles to stick to the punches (anti-sticking agents, anti-adherents)
Examples
- Talc and starch are good antiadherants, but not lubricant
- Magnesium stearate - both antiadherant and lubricant
105
Excipients: buffer & flavour
L10, pg 17
Buffering agens
- Change dissolution rate
- Change chemical stability in solution by altering the pH
Flavouring agents
- Give the tablet a more pleasant taste or mask an unpleasant taste
106
Excipients: colour
L10, pg 18
Colouring agents
- Provide aesthetic appeal and safety (improved differentiation b/w various tablet formulations)
- increase the stability of light-sensitive drugs
- Addition of colour as dissolved in the granulation liquid may lead to a colour variation in the tablet caused by migration of the soluble dye during drying stage
107
Excipients may be used for multi-purposes
L10, pg 19
Just have a wee look at this
Lactose: filler, binder
Microcrystalline cellulose (MCC): Filler, dry binder, (disintegrant, lubricant)
Calcium hydrogen phosphate dihydrate: Filler, dry binder
Starch: filler, binder, disintegrant, (lubricant)
Magnesium stearate: Lubricants, antiadherants, glidants
108
Consideration of excipients in the context of patients
L10, pg 21 + 22 + 23
Common adverse effecs associated w/ sorbitol include osmotic diarrhoea and gastrointestinal discomfort
An oral does of greater than 140mg/kg/day may result in gastrointestinal symptoms
Sorbitol is metabolised to fructose and is, therefore, unsuitable for patients with hereditary fructose intolerance
Lactose intolerance is the inability to digest lactose. The body has insufficient levels of lactase, an enzyme that helps digest lactose in the digestive system
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Patients will usually experience symptoms w/in 30 mins to 2 hours after eating. These include:
- Flatulence (wind)
- Bloating
- Tummy pain or discomfort
- Nausea (felling sick)
Diarrhoea (runny poos)
```
109
What is partitioning?
L 11, pg 3
- Distribution of solutes b/w immiscible solvents
- S(water) S(oil)
- Solute distributes in a definite concentration ration = partition coefficient (P)
110
How is "P" determined?
L11, pg 4 + 5
- Take a sample of oil and water and analyse for drug
| - P = [oil]/[water]
111
LogP
L11, pg 6
- Log of P, the partition coefficient
- Indicates the relative lipophilic/hydrophilic character or 'lipophilicity' of a compound
- A negative value for logP = hydrophilic
- When logP = 0 the compound is equally partitioned between the lipid and aqueous phases
- A positive value for logP = lipophilic
eg logP = 1 means there is a 10:1 partitioning in Organic : Aqueous phases
112
Pharmaceutical importance of logP
L11, pg 7
- Predicative of solubility
- Permeability (absorption) and accumulation of drugs in tissues -> bioavailability
- Plasma protein binding
- eg adipose tissues
- eg urine
- Adsorption to packaging
- Drug & preservative can partition formulation
113
Pharmaceutical importance of logP: general guideline
L11, pg 8
lkjhgf
114
Drug absorption & log P
L11, pg 9
kjhgf
115
Partitioning & preservatives efficacy
L11, pg 10
kjhgf
116
Preservatives (weak electrolytes)
L11, pg 11
To achieve effective control of micro-organism in the formulation, need to consider
- Extent of ionisation of the preservative
- pH of aqueous phase
- pKa of the preservative
- Unionised form = ACTIVE
117
Preservatives (weak electrolytes)
L11, pg 12
Unionised form = crosses bacterial wall
118
Introduce three main methods of tablet manufacturing:
* Direct compression
- Powder particles are directly compressed into tablets
* Compression of granules
- Powder particles are formulated as granules prior to the compression into tablets
- > Dry granulation
- Using pressure (often w/ binders)
- > Wet granulation
- Using solvents (often containing binders)
119
Direct compression
- diagram
L12, pg6
lkjhg
120
Granulation: Reasons for granulation
- TO IMPROVE FLOW PROPERTIES and reduce weight variation of tablets: Powders usually have poor flow property due to large surface area of small particles and their irregular size, shape and surface characteristics
- TO IMPROVE COMPRESSION CHARACTERISTICS: solute migration occurs during post granulation drying resulting in binder rich granule surface
- TO REDUCE HAZARD associated w/ toxic materials
- TO REDUCE CAKE FORMATION by hygroscopic powder
121
Dry granulation steps
- Diagram
L12, pg 8
lkjh
122
Wet granulation process
- Diagram
L12, pg 9
kjh
123
Compression: Rotary tablet press
- Have a wee look
L12, pg 10
kjhg
124
Characteristics of a good tablet:
- Contain the stated dose
- Be sufficiently strong
- Stable
- Biocompatible and free from unwanted contaminants, micro-organisms etc. that could harm patients
- Consistently deliver its dose of drug
- Attractive appearance, including colour, size, taste, etc, as applicable, to maximize patient acceptability
- Efficient, cost-effective, practical production of the required batches
- Be packed in safe manner
125
Appreciate the implications of tablets w/ poor quality
L12, pg 12
Therapeutic
- treatment failure
- side effects
Manufacturing
- Cost
- Time
126
Quality control - Tests are performed on each batch of tablets:
- Content of active ingredient
- Uniformity of content
- Uniformity of weight
- Tablet disintegration
- Tablet dissolution
- Friability
- Hardness
127
Content of active ingredient (official test)
- 20 tablets chosen at random, powdered together and assayed
- Limits depend on pharmacopeial monograph, but commonly must be between 90 & 110% of claimed content
- Note: this results in average value for active ingredient content over 20 tablets
128
Uniformity of content (official test)
- 10 tablets are assayed individually for amount of API
- BP, Eur, Ph.
- The content of 9 tablets should fall w/in 85 - 115% of average content
- 1 can fall w/in wider limit (75-125%)
- USP
- If not all 10, but only 9 tablets fall w/in specified limit, assay another 20 tablets: all must fall w/in limit
129
Uniformity of weight (official test)
- To help ensure each tablet has the same amount of drug
- 20 tablets, individually weighed
- Not more than TWO tablets permitted to deviate from mean by more than
- 10% if the tablet weight is < 80 mg
- 7.5%, if tablet weight is 80 - 250 mg
- 5%, if tablet weight is 250 mg or more
- Not more than ONE tablet permitted to deviate from mean by greater than twice the limit
130
Tablet disintegration (official test)
- To ensure drug is released from tablet appropriately
- 6 tablets
- Tablets are placed in tubes of disintegration tester
- Tubes are agitated in water bath
- Disintegration time limits
- Normal uncoated tablets: 15 mins
- Soluble tablets (intended to be dissolved before administration): 3 min
- Coated tablets: 30 min or 60 min
- Enteric coated tablet: should not disintegrate w/in 2 hours in 0.1 M HCI
131
Tablet dissolution (official test)
- Test is a measure of drug dissolving in a stated time under standardised conditions in vitro
- eg 80% in 30 min
- Dissolution = drug particles dissolve
- Key point - drug must be in solution to be absorbed
- Dissolution means solid drug going in to solution
132
Dissolution testing
L12, og 21
- Dissolution USP apparatus
- Solubility & dosage form type
- Standardized method
- Measure drug released into solution
- Different media
- Correlated to oral bioavailability
133
Friability (unofficial)
L12, pg 21
- Resistance to abrasion
- Tendency for tablet to chip, crumble or break on compression
- Tablets are subjected to a uniform tumbling action for a specified time (eg 100 turns) and the weight loss of the tablets is measured
134
Tablet hardness
- Breaking force
| - force required to break a tablet
135
Tablet defects
- Look at photos
L12, pg 24 & 25 & 26 & 27
Capping:
- The upper or lower segment of the tablet separates horizontally
Lamination:
- Separation of tablet into two or more layers
Cracking:
- Small fine cracks observed on the upper and lower central surfaces
Chipping:
- Breaking of tablet edges
Binding:
- Sticking of the tablet to the die and does not eject properly out of the die
Motting:
- An uneven distribution of colour on tablet surface
Double impression:
- Printing twice from the punches
Sticking:
- Tablet material adhering to the die wall
Picking:
- Product sticking w/in the letter, logos or designs of punch faces
136
Explain the reasons why coating of tablets is used:
1. Protect tablet ingredients
- Stability of API to protect from:
- Moisture
- pH etc
- During manufacture, transportation, storage and after administration
- Shelf life
2. Taste masking
- many drugs & excipients have a unpleasant taste
- Taste is a key feature that governs patient compliance
- Method for tast masking
- Film coating
- Sweeteners
- Polymers
3. Tablet identification
- Colour
- Shape
- Embossing / scoring
- Edible inks / dyes
Reasons
- Identification outside of packaging
- Protection from counterfeiting
- Distinction from competitors
4. Ease of swallowing
- Dysphagia
- Dry mouth
- Stroke, parkinsons disease, alzheimers disease
- Side effect of medications
- Lack of co-ordination
- Smooth small tablets are easier to administer
5. Functional coating
- To improve bioavailability
- Enteric coating
- Intact at low pH and release @ higher pH
- Small intestine is the primary site for drug absorption
- L13, pg 9
137
Some weird shit on L13, pg 10
Examples of tablet coating defects
L13, pg 12
- Film peeling
- Picking
- Twinning
eudragit
138
Implications of failure in coating
L13, pg 13
Therapeutic
- Treatment failure
- Side effects
Manufacturing
- Cost
- Time
139
Multiparticulates
L13, pg 17 & 18
- Pellets, granules, beads, spheroids...
- 150 um to 2-3 mm
- Single drug or multiple drug combinations
- Incorporated into a single dose unit of a hard gel capsule, sachet or in a compressed tablet
140
Advantages of multiparticulate drug delivery systems
- Flexibility in final product (capsule, sachet etc)
- Shelf stable w/out refrigeration
- Different coatings to give different release profiles
- Reduced dose variation due to more uniform gastric emptying and GI transit
- Facilitates more accurate dose titration
- Able to mix w/ food for easier swallowing
- Pediatric patients
- Geriatric patients
141
Fixed-dose combination (FDC)
- Delivery of 2 or more drugs in a single dosage form
- Combination drug product
- Improve patient adherence by reducing the pill burden
- ordering of medications is simplified
- L13, pg 21 (have a look @ example)
142
Soft gelatin capsules (softgels) vs Hard gelatin capsules
| - L13 , pg 14 & 15 23 & 24
kjhg
143
Formats for softgels
- Orally administered
- Solution or suspension filled for release in the stomach
- Chewable
- Highly flavoured w/ drug in fill matrix and/ or shell
- Twist-off
- A removable tag to release contents
- Meltable
- Suppositories that melt at body temperature
- Rectal administration
144
Rationale for choosing softgels
L13, pg 27
kjhgf
145
Complexation:
- Covalent or noncovalent interactions b/w one or more molecules of two compounds - a ligand and a substrate
- Ionic interactions
- H-bonding
- Van der waals forces
- LIGAND is a molecule that interacts w/ another molecule, the SUBSTRATE, to form a COMPLEX
146
Complexation - Causes & consequences
L14, pg 4
Complexation
Causes
- Changes in pH
- Changes in solvent
- Chelation
- Adsorption
- Interaction w/ container (eg plastic)
- In vivo (protein binding)
Consequences
- Changes in solubility
- Changes in efficacy (eg of preservatives)
- Changes in stability
- Changes intaste
- Changes in absorption or elimination
147
Types of complexes
1. Coordination complexes
- Covalent complexes that involve an ionic bond
2. Molecular complexes
- Noncovalent complexes formed by multiple attractive interactions (eg hydrogen bonding, electrostatic attraction, van der waals forces, or hydrophobic)
148
1. Coordination complexes
L14, pg 6 & 7 & 8
Metal complexes: eg clinical implications eg tertacycline (antibiotic)
- Divalent cations
- Drug = electron pair donor
- metal ion = electron pair acceptor
- dec. tetracyline solubility
- Reduced bioavailability, ie absorption from intestine into blood is reduced
Metal complexes
- most common coordination complexes
- Central metal atom or ion (often a cation) surrounded by -vely charged ions or neutral molecules (with lone pair of electrons)
149
2. Molecular complexes
L14, pg 9 & 10 & 11 & 12 & 13 & 14 & 15 & 16
- Noncovalent interactions b/w ligand and substrate
eg electrostatic attraction b/w oppositely charged ions, van der waals forces, hydrogen bonding , or hydrophobic interactions
Subdivided based on the substrate and ligand involved in complexation
- Small Molecule-Small Molecule Complexes
- Small Molecule-Large Molecule Complexes
- Large Molecule-Large Molecule Complexes
150
Systems of measure
L15, pg 4
kjh
151
Weight interconversions
L15, pg 5
mnb
152
Volume interconversions
L15, pg 6 & 7
,jhffds
153
Expressing concentration (strength)
L15, pg 8 & 9
kjhfdj
154
Percentages
L15, pg 10 & 11
deftgv
155
Preparing a % w/v product
L15, pg 12
- Dissolve the specific mass of the solute in a fraction of the solvent, then make up to volume with solvent
156
Calculations using % w/v
L15, pg 13 & 14 & 15 & 16 & 17 & 18 & 19 & 20 & 21
kjhytr
157
Hydrated compounds
L15, pg 22
kjkhjgh
158
Preparing a % w/w product
L15, pg 23
- Mix the specific mass of the solute in a fraction of the vehicle, then make up to volume w/ vehicle
159
Calculations using % w/w
L15, pg 24 & 25 & 26 & 27 & 28
defrdgtfh
160
Preparing a % v/v product
L15, pg 29
- Dissolve the required volume of the solute in a fraction of the solvent, then make up to volume with solvent
161
Calculations using % v/v
L15, pg 30 & 31
dftyfgf
162
Practice unit conversions
L15, pg 32 & 33 & 34 & 35 & 36 & 37 & 38 & 39
sdtfytu
163
Density
L16, pg 41 & 42
Density, p = Mass/Volume
164
Molarity (M)
L16, pg 43 & 44 & 45
- Number of moles of a component in 1 litre (1000mL) of solution
- Molarity (M) = No. of moles (n)/Volume (L)
- No. of moles (n) = Mass (g)/ Molecular weight (gmol-1)
165
Calculation using % w/v percentages: hydrated compounds
L16, pg 46 & 47
lkjh
166
Mole fraction (X)
L16, pg 48 & 49 & 50
Ratio of the number of moles of a component (A) to the total number of moles (A+B) of all components w/in the system
167
Parts components
L16, pg 51 & 52 & 53 & 54 & 55
- A part is the mass or volume of a component in a mass or volume of a product
168
interfacial phase (an interphase)
L17, pg 5
- When phases exit together ('equilibrium') the boundary between two phases = interfacial phase (an interphase)
169
Why is boundary b/w two phases an interphase?
L17, pg 6
- Changes are continuous but often modelled as discontinuous (a border)
- Physical-chemical properties change at an interface
170
Types of interfaces
L17, pg 7
- Gas-liquid = liquid surface eg water exposed to atmosphere
- Gas-Solid = solid surface eg bench top
- Liquid-liquid = liquid-liquid interface eg emulsions
- Liquid-solid = liquid-solid interface eg suspension
171
Significance of interfacial phenomena in pharmacy
L17, pg 8
wqefrgt56y
172
Surface and interfacial phenomena "boundary issues in pharmacy"
1) surface and interfacial tension
2) Wetting and Spreading
3) Adsorption
173
1. Surface tension (y)
L17, pg 10
'elastic sheet'
174
Forces at play
1) Cohesive forces
2) Adhesive forces
Forces at play
1) Cohesive forces
- Forces b/w like molecules
- intermolecular forces e.g H-bond , van der waals forces
2) Adhesive forces
- Forces b/w unlike molecules
- Mechanical, electrostatic forces
175
Cohesive forces
L17, pg 12 & 13
- In the bulk - net cohesive force of ZERO (equal in all directions)
- Molecule is pulled equally in all directions by neighbouring molecules
176
Cohesive and adhesive forces:
L17, pg 14
- Surface molecules are unequally attracted to other molecules
- Cohesive forces (not in equal directions)
- Adhesive forces
177
Definition: surface tension (y)
L17, pg 15 & 16
- Adhesive forces are weak
- Pulls the molecule of the interface together --> contracts the surface or creates 'tension in the surface'
- Inwards force directed toward the bulk
178
Interfacial tension (YLL)
L 17 pg 17
- The force per unit length existing at the interface between 2 immiscible liquid phases
179
2. Wetting and Spreading
L17, pg 18
- How a liquid deposited on a solid or liquid substrate spreads out
180
Why is wetting important?
- Coating of tablets (coat spreads over tablet)
| - Lotions/creams need to wet tissues or skin
181
Wetting
- L17, pg 20
- Whether one liquid will "spread: on another depends on the relative magnitude of the COHESIVE FORCES and ADHESIVE forces existing b/w the two liquids
Film:
- Adhesive forces > Cohesive forces(liquid)
Drop/lens:
- Adhesive forces < cohesive forces (liquid)
182
Contact angle (0)
- L17, pg 21 & 22
- Angle = 0: complete wetting
- Angle < 90: low values of angle (<90*) indicate that the liquid spreads or wets the solid surface well
- angle = 180*: Insignificant wetting
- The angle formed b/w a liquid droplet and the surface over which it spreads
- Quantitative measure of the wetting of a solid by a liquid - 'wettability'
degree = 0: complete wetting
183
Wetting agents eg in a suspension
- L17, pg 23
- A compound that lowers the contact angle b/w the particle surface and the liquid (ie promotes wetting)
- Surfactants
- Alcohol
- Glycerin
- eg surfactants acting to lower tension
184
3. Adsorption
- Interfacial or surface phenomena - the process of accumulation at an interface
185
Adsorption at solid interfaces
May take place from an adjacent liquid or gas phase
- ADSORBATE: substance that adsorbs onto the solid surface
- ADSORBENT: solid onto which the substance is adsorbed
186
Adsorption vs Absorption
L17, pg 26
Adsorption
= Accumulation at/on a surface 'surface effect'
Absorption
= Movement into another material or phase
'penetration'
187
Types of adsorption
Chemical (chemisorption):
Physical:
Types of adsorption
Chemical (chemisorption):
- Adsorbate is bound via strong primary forces
- Specific binding, may require an activation therefore slow and not readily reversible
Physical:
- Adsorbate is bound via weak secondary forces- - Readily reversible - removal of adsorbate from the adsorbent is a process known as desorption
188
Pharmaceutical applications of adsorption:
- Preventing absorption after oral overdose and poisoning (eg activated charcoal)
- Formulation stability eg wetting agents
189
Unwanted applications of adsorption
- Adsorption of drugs by adsorbents taken simultaneously by a patient
- Adsorption of drugs onto the walls of a container
- Adsorption of drugs onto excipients
190
# Define what is a pharmaceutical dispersion
Dispersion:
- Pharmaceutical dispersions are systems where one substance is dispersed within another substance
- Where the dispersed phase, typically a particle of some type, which is physically distinguishable from the medium in which it is dispersed
- Differ from true solutions which are homogenous molecular dispersions - the true solutions
- Dispersions are heterogenous systems - as exemplified by suspensions and emulsions
191
Colloidal dispersions
L18, pg 8
- A system in which one substance (dispersed or 'internal' phase) is distributed throughout another ( Dispersion medium or 'external' or 'continuous phase')
192
What are dispersions?
Examples:
- A dispersion is made by mixing together 2 or more ingredients that are not mutually miscible and are capable of forming homogenous solutions
Examples:
- Suspension (solid in liquid)
- Emulsions (liquid in liquid)
- Foams (vapour in liquid)
193
Colloidal dispersions
- Have a wee look
L18, pg 11
lkjh
194
Properties of dispersion
- have a wee look
L18, pg 12
lkjhg
195
Classification of colloidal dispersions
There are three types of colloidal dispersions (1 nm - 0.5 um):
1) Lyophilic colloids (hydrophilic)
2) Lyophobic colloids (hydrophobic)
3) Association colloids
196
Lyophilic colloids:
L18, pg 16 & 17
- Dispersed phase is solvent loving ('hydrophilic' if water
- Significant interaction between the dispersed and the continuous phase
- Form spontaneously
- Thermodynamically stable
197
Lyophobic colloids:
L18, pg 18 & 19
- Dispersed phase is solvent hating (hydrophobic)
- Minimal interaction between the dispersed and the continuous phase
- Do not form spontaneously
- Thermodynamically unstable (tendency to aggregate)
198
Examples of colloidal dispersions
L18, pg 21
Used as drug-delivery systems
- Liposomes (0.15-0.5 um)
- Micelles (<100nm)
- Nanoparticles 2-100nm
199
Associate colloids
- L18, pg 22
A commercial example of the use of microemulsion to help solubilize a drug is the product Neoral (cyclosporine), an immunosuppressant
200
Properties of colloidal dispersions
- Have a wee look
L18, pg 23
knjbhgv
201
Optical properties
L18, pg 24 & 25
- Scattering of light by the colloidal particles -> a visible cone -> faraday tyndall effect (F-T effect)
202
Coarse dispersions
- Suspension
| - Emulsions
203
Supensions:
L18, pg 28
- A pharmaceutical suspension is a COARSE DISPERSION in which INSOLUBLE SOLID PARTICLES are dispersed in a LIQUID MEDIUM
204
Emulsions
L18, pg 29
- Coarse emulsions, termed simply emulsions, are mixtures of IMMISCIBLE LIQUIDS, in which one phase (liquid) is dispersed as droplets within the other phase (liquid)
205
Stokes' Law of sedimentation
- Idk if I need to know it
L18, pg 31
- to determine the rate of sedimentation
206
Application of Stokes' Law
Determination of
- Settling rate in suspension
- Creaming rate in emulsion
207
Brownian Motion
- idk if i need to know this
Brownian motion is the random motion of particles suspended in a fluid (a liquid or a gas) resulting from their collision with the fast-moving molecules in the fluid
- Temperature, medium viscosity, and dispersed particle size
208
Stokes law assumptions
Stokes law holds exactly only for:
L18, pg 35 & 36
- Spherical particles
- Influence of gravity
- Free fall at constant rate
- Laminar or streamline flow around particles
209
Aggregation and its consequences:
L19, pg 4 & 5
- A stability concern of dispersed systems is that the dispersed particles are drive to aggregate - reversibly in some cases and irreversibly in others
- An irreversible particle growth can compromise formulations in many ways
210
Have a wee read of Interfacial properties
L19, pg 7
Particles moving in a dispersion will collide with each other with varying frequency and force, as functions of temperature, particle size, particle conc., dispersion medium viscosity, and other properties
- Each collision can lead to particle cohesion with varying cohesive strength, depending on the attractive and repulsive nature of the particle surfaces
211
Importance of DLVO theory
- Understanding interfacial properties of the particles need to understand the DLVO theory
- Is critical in order to understand the stability of dispersions
- It can be applied to colloids (hydrophobic only)*, suspensions and emulsions
212
Basis of the DLVO theory
L19, pg 10
- Stability of hydrophobic colloidal dispersions
| - Forces of interaction between colloidal particles
213
DLVO theory of colloidal stability
- The DLVO theory describes (quantitatively) the combined effect of repulsive and attractive force in relation to lyophobic colloids
214
Basis of the DLVO theory
L19, pg 12
- The van der waals forces, which are the main attractive forces between particles, arise from transient fluctuations in electron density, which can create instantaneous dipole moments in a molecule . these instantaneous dipole moments can induce polarization of neighbouring molecules, resulting in the correlated interaction (attraction) of the dipole and induced dipole
215
Basis of the DLVO Theory
- Diagram
L19, pg 13
- Electrostatic attractive forces
| - Electrostatic repulsive forces
216
Ionization
L19, pg 14 & 15
- Ionizable groups at surface of the particle such as carboxyl, amino, hydroxyl, sulfonic, will influence the surface charge
- The charge here is usually dependent on pH
217
DLVO Theory
- Repulsion curve, VR:
- Attraction curve, VA:
- Composite cure, VT:
- Graph
L19, pg 16 & 17 & 18 & 19
DLVO Theory
Repulsion curve, VR:
- Dependent on z-potential or surface charge of the particles
Attraction curve, VA:
- independent of surface charge
- Dependent on chemical nature, size and distance of the particles
Composite cure, VT:
- Net interaction energy = sum of VR and VA
218
How is it possible to influence the stability of the dispersion?
- By changing the Z-potential
| - Or better: the repulsive forces in general
219
Importance of Zeta Potential:
- Governs the degree of repulsion b/w adjacent, similarly charged, dispersed particles (ie stability of colloidal systems)
- Can be manipulated by pH and ionic strength
220
manipulating zeta potential
Effect of electrolytes:
Concentration of electrolytes
- The higher the electrolyte concentration present in the system, the higher the screening effect of the counterions
Valency of the counterion
- The higher the valency of the counterion (eg Na+ vs MG2+ at a constant total electrolyte concentration, the. higher the screening effect
221
Non-DLVO forces
- Hydration forces
| - Steric forces
222
Non-DLVO Forces
Hydration forces: important for hydrophilic colloids
L19, pg 23
fhbjkncds
223
Non-DLVO Forces
Steric forces
L19, pg 24
kijouhy
224
Pharmacy example
L19, pg 25
fdbvns
225
Semi-solid dosage forms: introduction and application
- Products of semi-solid consistency
- Semi-solid preparations are intended for LOCAL or TRANSDERMAL DELIVERY of active substances, or for their EMOLLIENT or PROTECTIVE action
226
Semi-solid dosage forms: common ingredients and excipients
- Semi-solid preparations consist of a simple or compound BASIS in which, usually, 1 or more active substances are DISSOLVED or DISPERSED
- The basis may consist of natural or synthetic substances and may be SINGLE PHASE or MULTIPHASE
- According to the nature of the basis, the preparation may have HYDROPHILIC or HYDROPHOBIC properties
- It may contain suitable excipients such as ANTIMICROBIAL PRESERVATIVES, ANTIOXIDANTS, STABILISERS, EMULSIFIERS, THICKENERS and PENETRATION ENHANCERS
227
Classification of semi-solid dosage forms
Several categories of semi-solid preparations:
- Creams
- Gels
- Ointments
- Pastes
- Plasters
- Glycerogelatins
- Poultices
228
Creams: types
Lipophilic:
Hydrophilic:
Creams: types
Lipophilic:
- W/O emulsions ie - Continuous phase is a lipophilic. They usually contain water-in-oil emulsifying agents such as wool alcohols, sorbitan esters and monoglycerides
Hydrophilic:
- O/W emulsions ie, the continuous phase is the aqueous phase. They contain oil-in-water emulsifying agents such as sodium or ...
229
Cold creams:
- W/O emulsions, when applied on the skin, a cooling effect is produced due to slow eveporation of water
Common ingredients
- Water
- Oily parts
- Beeswax
- Emulsifying agent
- Perfumes and preservatives
230
Vanishing Creams
- O/w emulsions - when rubbed into the skin, water evaporates leaving a very thin layer of stearic acid
Composition
- Stearic acid
- Water
- Emulsifying agent
- Glycerine
- prevents chaps
- Acts as a humectant
231
Creams: how formulation influences the effectiveness of creams
L20, pg 12 & 13
- Vanishing creams have a non-oily feel
- Cold creams can give a greasy feel. If the skin is low in oil, cold creams can be used
- Oily creams (w/o emulsions are less greasy than ointments, are easier to apply, and can usually be simply washed off the skin surface, and hence well accepted by patients. however, whilst the w/o creams can deposit a protective oily layer on the surface, they tend to be less occlusive than an ointment and so may not be beneficial in dry skin conditions
- Creams usually include an antimicrobial preservative, a buffer, an antioxidant & fragance materials
- Creams should not normally be diluted. However, should dilution be necessary care should be taken, in particular, to prevent microbial contamination. The approriate diluent should be used and heating should be avoided during mixing. Excessive dilution may affect the stability of some creams. If diluted, creams should normallly by used w/in two weeks of their preparation
- creams should not be allowed to freeze
232
Gels
L20, pg 16
Gelling agents
- Synthetic macromolecules such as carbomer 934
- Cellulose derivatives such as carboxymethylcellulose (CMC) or hydroxypropyl methylcellulose (HPMC)
- Natural gums such as tragacanth
- Gels are semisolids consisting of small or large molecules dissolved (single-phase_ or dispersed (two-phase) in an aqueous system by a gelling agent
- The liquid forms a continuous phase with the thickening agent enhancing viscosity by providing porous scaffold of the gel
233
Components of gels
- may contain drug
- Gelling agent
- Water
- Solvents
Stabilizers
Storage
- Gels should not be allowed to freeze
234
Types of gels
Lipophilic gels:
Hydrophylic ges:
Types of gels
Lipophilic gels:
- Lipophilic gels (oleogels) are preparations whose bases usually consist of liquid paraffin with polyethylene or fatty oils gelled with colloidal silica or aluminium or zinc soaps
Hydrophylic ges:
- Hydrophilic gels (hydrogels) are preparations whose bases usually consist of water, glycerol or propylene glycol gelled w/ suitable gelling agents
235
Medicated gels can be administered by various routes:
- Nasal
- Opthalmic
- Vaginal
- Rectal
236
Physical Stability of suspensions
Defined as:
L21, pg 9
- The condition in which the particles do not aggregate and in which they remain uniformly distributed thoughout the dispersion
237
Physical properties:
L21, pg 10
Suspensions are thermodynamically unstable systems and the goal is to design a preparation that is kinetically stable for a sufficient period of time (shelf-life) so that the product performance is not compromised by gross changes in physical properties
- Caking
238
Agglomerates
L21, pg 11
Floccules - "flocs"
- Flocculated
Aggregates "cake"
- Deflocculated
239
Comparison of deflocculated/flocculated suspension
Deflocculated suspension:
Flocculated suspension:
L21, pg 12 & 13 & 14 & 15
Comparison of deflocculated/flocculated suspension
Deflocculated suspension:
- The dispersed particles remain as individual DISCRETE PARTICLES
Flocculated suspension:
- The dispersed particles come together to form large clumps or FLOCS
240
Deflocculated Suspension:
Advantage:
Disadvantage:
Deflocculated Suspension:
Advantage:
- Discrete particle sediment slowly
Disadvantage:
- Caking upon standing
241
Flocculated suspension:
Advantage:
Disadvantage:
Flocculated suspension:
Advantage:
- Sediment re-disperses easily with shaking
- Made in a factory reduces cost
Disadvantage:
- Flocs sediment quickly
242
Deflocculated & Flocculated examples
L21, pg 19 & 20 & 21
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243
Formulation Control:
L21, pg 22
- Stokes law of sedimentation
244
Formulation Control
Properties under control of formulator:
- State of flocculation
- Particle size of the dispersed phase
- Viscosity of the continuous phase
245
Formulation Control
Methods to improve the properties of a suspension:
- Inclusion of viscosity inducing agents (suspending agents) to retain deflocculated particles in suspension
- Encourage flocculation
- Use of viscosity inducing agents to retain flocculated particles in suspension
- Particle size reduction by milling
246
Suspension Formulation Model
L21, pg 25
Suspensions
- Dispersed phase
- Continuous phase
247
Suspension Composition I
Composition of typical suspension:
* Dispersed phase (insoluble drug)
*Continuous phase (usually water)
Suspension Composition I
Composition of typical suspension:
* Dispersed phase (insoluble drug)
- Wetting agents
- Flocculating agents
* Continuous phase (usually water)
- Suspending agents
- Preservatives
248
Suspension Composition II
In addition to the previous excipients, suspensions often contain:
- Sweetening agents
- Colouring agents
- Flavouring agents
249
Dispersed Phase
Important to consider:
- Compatibility of the drug with other excipients
- Particle size
- Sedimentation rate
- Ionic character
- Zeta potential
- Initial step in manufacturing a suspension: dispersion of insoluble powder
- wetting
250
Wetting particle
Use wetting agents such as:
Wetting particle
Use wetting agents such as:
- Surfactants HLB 6-9
- Alcohol
- Glycerin
251
Wetting agents
- Read L21, pg 30
- Wetting of hydrophobic particles requires adsorption of the wetting agent at the solid surface
- A wetting agent is a compound that when dissolved in water LOWERS THE CONTACT ANGLE b/w the particle surface and the liquid and aids in displacing an air phase at the solid surface, and replaces it with a liquid one
252
Wetting agents
L21, pg 32 + 33 + 34 + 35 + 36 + 37
Wetting agents for oral use:
- Tweens
- Spans
Surfactants for external (topical) use
- Sodium lauryl sulfate
- Sodium dioctyl sulphosuccinate
Wetting agents
- Surfactants (HLB: 6-9)
- Water-miscible solvents
- Non-toxic, non irritant
water-miscible solvents
- These liquids flow into the voids b/w particles and displace air
- They coat and separate individual particles so that water can penetrate and wet particles
- Alcohol
- Glycerol
- propylene glycol
253
Flocculation of dispersed phase
L21, pg 38
Assuming that the powder is properly wetted and dispersed, we can now consider the various means by which controlled flocculation can be produced so as to prevent formation of a compact sediment (cake) that is difficult to redisperse
254
Controlled Flocculation:
- State in which attractive and repulsive forces are BALANCED
- ATTRACTIVE FORCES must be large enough to cause flocculation
- REPULSIVE FORCES must be sufficiently high enough to prevent close contact (aggregation) but low enough so that ATTRACTIVE FORCE IS DOMINANT
255
Flocculating Agents:
- Surfactants
- Electrolytes
- Polymers (hydrophilic colloids)
- Concentration of these compounds necessary to achieve flocculation is critical
256
Flocculating Agents:
Non-ionic (hydrophilic colloids):
Ionic (electrolytes):
- Ionic and non-ionic agents can act as flocculating agents
- Adsorb onto the surface of hydrophobic dispersed particles
Non-ionic (hydrophilic colloids):
- May adsorb on to more than one particle
- Link them together in a loosely arranged structure
Ionic (electrolytes):
- Alter the Z-potential
- If sufficiently lowered, flocculation occurs
257
Polymers
L21, pg 42
- Hydrophilic polymers
- Linear branched-chain molecules adsorb on to the surface of the dispersed particles
- link them together in a loosely arranged structure
- Starch
- tragacanth
- Alginates
- Cellulose derivatives
- Simply a physical bridging affect
- Also used as suspending agents
258
Electrolytes
L21, pg 43
- Electrolytes act as flocculating agents
- by reducing the electric barrier b/w the particles
- Alteration of the z-potential
- effectiveness depends on valency
- Sodium salts of
- acetates, phosephates, citrates
- Lowering the zeta potential will bring about flocculation by lowering the energy barrier
259
Controlled flocculation
L21, pg 44
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260
Pharmacy example
L21, pg 45
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261
Suspension Composition:
Composition of typical suspension:
Dispersed phase (insoluble drug)
- Wetting agents
- Flocculating agents
Continuous phase (usually water)
- Suspending agents
- Preservatives
262
Continuous Phase:
- Particles in a dispersion will settle under the influence of gravity as a function of their particle size --> stokes law
- Flocs are large, therefore they will settle rapidly --> Undesirable
- Particle sedimentation can be slowed down by the addition of a suspending agent (viscosity inducing agent)
263
Examples of Suspending Agents
L22, pg 6 + 7 + 8
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264
Properties of the ideal suspending agent
- Suspending agents are materials added to a suspension to increase viscosity and retard sedimentation
- Many materials that fall into this classification-Natural and Semi-synthetic
- Most suspending agents are either neutral or negatively charged
- Generally effective in a concentration range of 1 to 5 %
265
Properties of the ideal suspending agent:
- easily and uniformly incorporated into the formulation
- Easily dissolved or dispersed in water w/out the need to resort to specialised mixing techniques
- Inert
- Non-toxic
- Must be compatible w/ other components of the formulation
266
Rheological Considerations
Suspending agents
Rheology of suspensions:
L22, pg 11 & 12
- Ideally high apparent viscosity at low rates of shear and sufficiently low apparent viscosity at higher rates of shear to allow the suspension to be poured from the bottle
Important: reformation of initially high apparent viscosity after a short time to maintain adequate physical stability
- Thixotropic-pseudoplastic properties
267
Preservatives
Preservation of coarse dispersions
Possible incompatibilities:
- Interaction w/ wetting agents
- Interaction w/ poly
- Adsorption on to suspended particles
268
Guidelines for evaluation and assessment of suspension stability
Physical stability:
Quantitative assessment of flocculation:
Physical stability:
- Particle size & distribution
- Agglomeration
- Ostwald ripening
- Crystal growth
Quantitative assessment of flocculation:
- Sedimentation parameters
- Sedimentation volumes
- Sedimentation rates
- Ease of redispersibility of sediment
- measureing dose accuracy
269
Particle size and distribution
- Dispersed particles should all be relatively small and about the same size
- Slow settling rates
- Uniform settling rate
270
Particle size
L22, pg 19 + 20 + 21 + 22 + 23
- Large polydispersity = poor uniformity in sedimentation rate
- Small polydispersity = Greater uniformity in sedimentation rate
Particle size for a flocculated system
- Ideally smaller particles to reduce settling rate giving a greater opportunity for flocculation to occur before settling
Particle size for a non-flocculated system
- Ideally smaller particles to reduce settling rate giving a greater time the suspension remain homogenous
271
Particle size distribution
- Larger particles are more energetically stable than smaller particles
- Molecules on the surface of a particle are energetically less stable than the ones already well ordered and packed in the interior
- Large particles, with their lower surface to volume ratio, results in a lower energy state (and have a lower surface energy)
272
Crystal growth
L22, pg 25 + 26 + 27 + 28 + 29
- Drug solubility increases with rise in temperature
- > supersaturation
- On cooling drug will crystallize out
273
Particle size distribution on bio-pharmaceutical performance
- Size of particles will alter the rate and extent of absorption of drug particles
- Smaller particles will dissolve faster than larger particles due to the increased surface area per unit weight of the drug, thereby potentially increasing the rate and extent of drug absorption
274
Quantitative assessment of flocculation
L22, pg 31 + 32 + 33 + 34 + 35
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275
Redispersibility
- Ease of redisperibility is a major consideration in assessing the acceptability of a flocculated suspension
- Suspended particles will settle but settled particles must be easy to redisperse to give a uniform suspension so a correct dose will be administered
276
Redispersibility of pharmaceutical suspensions
- Many flocculated suspensions are liquid multi-dose containers
- Dosing accuracy of pharmaceutical suspensions depends mainly on the homogeneity of the dispersion
- Dosing accuracy is a measure of redispersibility
277
Types of dispersions
L23, pg 4
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278
Emulsions definition:
L23, pg 6
- A thermodynamically unstable system consisting of at least TWO IMMUSCIBLE PHASES, one of which is dispersed as globules (THE DISPERSED PHASE) in the other liquid phase (the continuous phase), stabilised by the presence of an emulsifying agent
279
Types of emulsions
2 basic types:
L23, pg 7
- Oil-in-water (o/w)
| - Water-in-oil (w/o)
280
Types of emulsions
2 multiple types:
L23, pg 8
- Water-in-oil-in-water (w/o/w)
| - Oil-in-water-in-oil (o/w/o
281
Sustained release - w/o/w
L23, pg 9
- Water soluble drug entrapped in the internal water, oil phase would act as diffusion barrier slowing down release
282
Choice of emulsion type:
L23, pg 10 & 11
Oral
- mainly o/w
- Administrations of oils as such or as vehicles for oil-soluble drugs
Parenteral
- Intravenous
- Must be o/w
- Intramuscular
- Can be either
- Subcutaneous
- Can be either
External
- Widely used (creams, lotions, liniments
- Can be either
283
Emulsions
What do they mask?
Extended release of drug after?
Essential nutrients like .... can all be emulsified and can be administered as sterile intravenous emulsions
Emulsions are used widely to:
- Mask the bitter taste and odour of drugs, thereby making them more palatable
- After injection IM or SC
- Carbohydrates
- Fats
- Vitamins
- Used to formulate externally used products
- Lotions, creams, liniments etc
284
Ideal Emulsions
Properties:
- Remains SUFFICIENTLY HOMOGENOUS to allow removal of a dose
- Creaming produced on storage must be EASILY REDISPERSED
- Is CHEMICALLY AND PHYSICALLY STABLE for the shelf-life
- POURS EASILY from the container
- Topical application: SPREADS EASILY, DRIES QUICKLY, ACCEPTABLE COLOUR & ODOUR
285
Interfacial Properties of emulsions
Why do these two liquids fail to remain mixed after shaking?
L23, pg 17
- The cohesive forces b/w molecules of each separate phase (oil-oil, water-water) are greater than the adhesive forces b/w the two liquids (water-oil)
286
Methods to produce an emulsion
Breaking of liquid into droplets and disperion in continuous medium required work
- Shaking in a bottle
- Mortar and pestle
- High speed mixers and blenders
- Homogenisers
287
Interfacial properties of emulsion
L23, pg 19
- Breaking of liquid into droplets and dispersion in continuous medium requires WORK
- Large surface area --> High surface free energy ---> Thermodynamically unstable
- To reach a more thermodynamically stable state, droplets attempt to reduce the surface free energy and decrease the surface area --> COALESCENCE
288
Coalescence =?
L23, pg 20
- Fusing together of droplets to form larger droplets
289
Emulsifying agents:
- A substance that stabilizes an emulsion by increasing its kinetic stability
- Excipients which go into the WATER-OIL interface to form a FILM around the dispersed globules
- Surface active agents
- Hydrophilic colloids
- Finely divided solids
290
Emulsifying Agents
Surface tension & repulsion theory
Physical barrier theory & Viscosity theory
L23, pg 22 & 23
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291
Surfactants
L23, pg 24
- Adsorb at the oil-water interface to form a . monomolecular film and reduce interfacial tension
292
Surfactants
Prevent coalescence of dispersed droplets by:
- Reducing interfacial tension
- Forming a coherent film around the dispersed phase which acts as a physical barrier to coalescence
- If charged: additional repulsive effect
293
W/O vs O/W Emulsions
- Bancrofs rule
- The emulsifier is more soluble in the continuous phase
- High HLB surfactants-emulsifying agents are more soluble in water than in oil (O/W emulsion)
- Low HLB surfactant-emulsifying agents are more soluble in oil than water (W/o emusion)
294
Surfactants
- The type of emulsion formed depends on the ... of the surfactant
L23, pg 27
Surfactants
- The type of emulsion formed depends on the HYDROPHILE-LIPOPHILE BALANCE (HLB) of the surfactant
295
Hydrophilic colloids (hydrophilic polymers dispersed in water):
L23, pg 28 & 29
Adsorb @ the oil-water interface to form a strong physical barrier (FILM) around the dispersed droplets of oil in an O/W emulsion
296
Finely Divided Solids:
L23, pg 30 & 31
- Adsorptiion at the interface to form a coherent film of particles around the dispersed droplets that physically prevents coalescence
297
Ointments: Introduction
- Ointments are semisolid preparations for external application to the skin or mucous membranes
- An ointment consist of a SINGLE-PHASE BASIS in which solids or liquids may be dispersed
- Ointments are usually occlusive and are generally used on DRY LESIONS
- occlusive = which creates a barrier b/w skin and the air
298
Unmedicated and medicated ointments:
Unmedicated ointments:
- Are used for the physical effects they provide as protectants, emollients (to soothe, smooth and hydrate dry skin), or lubricants
Medicated ointments:
- May contain one or more active ingredient(s)
299
Types of ointment bases
- Oleaginous bases
- Absorption bases
- Water-removal bases
- Water-soluble bases
300
Oleaginous bases
- Oleaginous bases are HYDROCARBON BASES
- REMAIN ON THE SKIN for long periods w/out drying out
- DIFFICULT TO WASH OFF
- Water or aqueous preparations can be incorporated, but ONLY IN SMALL AMOUNTS and w/ difficulty
- Examples: Petrolatum, white petrolatum & yellow ointment
Uses:
- EMOLLIENT effect
- Prevent TRANSEPIDERMAL ESCAPE OF MOISTURE
ie, hydrate skin
- Effective as OCCLUSIVE dressing
301
Absorption bases:
- Generally contain a HYDROCARBON such as paraffin together with A MISCIBLE EMULSIFYING AGENT that is polar eg sorbitan monooleate
- It allows to SOAK UP WHILE REMAINING SEMI-SOLID UP TO 15% WATER or AQUEOUS SECRETIONS
- DIFFICULT TO WASH OFF
- USEFUL AS EMOLLIENTS although they DO NOT PROVIDE THE OCCLUSION LIKE OLEAGINOUS BASES
302
Absorption bases are two types:
a) Allow the incorporation of aqueous solutions to FORM WATER-IN-OIL (W/O) EMULSIONS (eg, hydrophilic petrolatum)
a) W/O EMULSIONS that allow the incorporation of additional quantitie of aqueous solutions (e.g, lanolin)
303
Water-removable/washable bases
- OIL-IN-WATER (O/W) EMULSIONS resembling creams
- EASILY washed from skin since the external phase is water
- CAN BE DILUTED W/ WATER
- ABSORB SEROUS DISCHARGES
- Examples: Hydrophilic ointment, USP
304
Water-soluble bases
- No oleaginous components (greaseless)
- NO oleaginous components (greaseless)
- Prepared from a MIXTURE OF POLYETHYLENE GLYCOLS which soften when applied to the skin surface
- MIX EASILY WITH SKIN SECRETIONS, SPREAD EASILY ON SKIN AND READILY WASEHD OFF
- Soften with water, so LARGE AMOUNTS of aqueous solutions ARE NOT effectively incorporated in these bases
- LOSE THEIR SEMISOLID CONSISTENCY IF APPROX 10 % WATER is taken into ointment
- Examples: Polyethylene glycol ointment, NF
305
Ophthalmic ointment base - desired characteristics
- Must not be irritating to the eye
- Must permit the diffusion of the medical substance throughout the secretions bathing the eye
- Should have a softening point close to body temperature, both for comfort and for drug release
- Ointment must be sterile although all oinments should not contain S. aureus or P.aeruginosa
306
Different types of ointments
Hydrophobic:
Hydrophilic:
Different types of ointments
Hydrophobic:
- Made of oleaginous bases
- Absorb small amount of water
Hydrophilic:
- Water soluble bases
- The bases usually consist of mixtures of liquid and solid macrogols (polyethylene glycols). They may contain appropriate amounts of water
307
Different types of ointments
Water emulsifying ointments:
- Able to absorb larger amounts of water
- Absorption bases
- Can form w/o or o/w emulsions which depends on the emulsifying agents
- w/o emulsifying agents: wool alcohols, sorbitan esters, monoglycerides and fatty alcohols
- o/w emulsifying agents: Sulfated fatty alcohols, polysorbates, macrogol cetostearyl ether or esters of fatty acids with macrogols may be used for this purpose. Their bases are those of the hydrophobic ointments
308
USES for ointments
- Hydrophobic ointments and water-emulsifying ointments are intended to be applied to the skin or certain mucous membranes for EMOLLIENT, PROTECTIVE, THERAPEUTIC or PROPHYLACTIC purposes where a degree of occlusion is desired
- Hydrophilic ointments are miscible with the skin secretion and are less emollient as a consequence
- Ointments should not normally be diluted. However, if dilution is necessary, select diluents carefully to avoid risk of incompatibility or instability
309
How the formulation influences choice of ointments of a patient
- Thick greasy ointments are difficult to spread, particularly damaged or broken skin, where they are commonly applied, and patients often find these formulations are messy to use
310
Method of incorporating active ingredient into ointment bases
Incorporating solid drug:
Incorporating liquids:
Method of incorporating active ingredient into ointment bases
Incorporating solid drug:
1) Spatulation
2) Ointment mill
Incorporating liquids:
- Consider base capacity to accept the volume required
311
Pastes introduction & examples
L25, pg 19
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312
Plasters: introduction & examples
L25, pg 20 & 21 & 22
uhytgrf
313
Glycerogelatins: Introduction & examples
L25, pg 23
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314
Packaging of ointments and creams:
- Jars - Clear or opaque glass or plastic - opaque jars are porcelain white, dark, green or amber coloured. Used for LIGHT-SENSITIVE PRODUCTS
Tubes - aluminium or plastic-light in weight, inexpensive-convenient-compatible with most formulation components-prove GREATER PROTECTION AGAINST EXTERNAL CONTAMINATION AND ENVIRONMENTAL CONDITIONS
- Syringes-accurate quantity can be dispensed
315
Tests for emulsion type - Miscibility Tests
L24, pg 7
uhigyu
316
Tests for emulsion type - Viscosity Test
L24, pg 8 & 9 & 10
njfjdc
317
Tests for emulsion type - Staining tests
L24, pg 11
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318
Conductivity Tests
L24, pg 11
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319
Types of emulsion instability
- Flocculation
- Creaming
- Cracking (=Breaking; coalescence)
- Phase inversion
320
Creaming
L24, pg 16 & 19 & 20
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321
Floculation
L24, pg 17 & 18
Problems associated w/ flocculation
- Flocculation precedes coalescence
- Increase likelihood of creaming because aggregates behave as a single large droplet whose density differs from that of the continuous phase
322
Cracking (breaking)
L24, pg 21 & 22 & 23
ehf
323
Emulsion Instability
L24, pg 24
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324
Phase inversion
L24, pg 25 & 26 & 27 & 28
Causes of phase inversion
- Addition of an electrolyte which alters HLB of a surfactant
- Change in temperature can alter the HLB of a surfactant
- Changing the phase-volume ratio
325
Emulsion physical stability
L24, pg 29
fcdre
326
Stress testing
L24, pg 31
Droplet size and size distribution
- Use microscope or coulter counter or laser diffraction sizing
- Inc. size = dec. number count --> coalescence
Viscosity
- dec. droplet size = inc. viscosity
- inc. size distribution = dec. viscosity
327
Rheologic properties
L24, pg 32 & 33
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328
Formulation control
L24, pg 34 & 35 & 36
- Avoidance of creaming
- Avoidance of flocculation
- Avoidance of coalescence/breaking
329
Pharmaceutical product can be:
Non - Sterile:
- Not required to be sterile but must not contain any objectionable microbes
- Need good manufacturing practices (GMP) to control this
- Have qualitative standards (for specific pathogens) and quantitative standards (how many are allowed)
330
GMP
L26, pg 2 (but 7)
- High assurance of quality of a product is gained from controlling all steps of the manufacture, rather than from selective testing of the final product
331
Maybe have a look at L26, pg 2 (but 8)
Steps of manufacture
332
Pharmaceutical products can be
Sterile:
- Free of microbes (& also pyrogens, dust etc)
- Injections
- IV fluids, parenteral nutrition
- Eye and ear solutions
- Surgical dressings & sutures
- Implants
- Sterile aerosol products
333
Manufacture of sterile products
2 options:
L26, pg 2 (but 10)
1) Terminal sterilisation - make the product (non-sterile GMP), package then sterilise
2) Aseptic manufacture - make the product using sterile components using aseptic processing
334
Aseptic manufacture used when:
- Active can not be terminally sterilized
- Require a large degree of operator input
- Is used to make personalized products
335
Examples of aseptic processes:
- Manufacture/formulation - large scale & personalized (eg immunotherapies)
- Compositing - many into one
- Filling & splitting - one into many
- Sampling - remove part of contents
- Transferring - change containers
336
Why don't we want microbes in our medicines?
They can cause:
L26, pg 3 (but 13 - 16)
They can cause
- Infections
- Inflammation
- Degredation (chemical & physiochemical) of drug & excipients - fats, oils, sugars
- Changes can be visible (slimy, gritty, discoloration) or may change the smell or taste of the medicine
337
Sources of contamination - Personnel
L26, pg 3
- Microbes are part of the human microflora (skin, GI tract)_ and personnel can carry pathogens
Controlled by
- Limiting access
- Use of PPE (gowns, gloves, hats, masks)
- Training
338
Sources of contamination - Air
- Facilities have humidity, ventilation, air conditioning units (HVAC), laminar flow cabinets
- Filter out bacteria and dust-bacteria
- Control humidity so no water droplets-bacteria
- UV irradiate air
339
HVAC & HEPA
L26, pg4 (But 22 & 23)
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340
Fume hood vs laminar flow hood vs biological safety hood
L26, pg 4 & 5
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341
Buildings and equipment
L26, pg 5
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342
Sources of contamination - Materials & H20)
Raw materials & water will contain microbes
Control by:
- Sampling and testing
- Chemically treat & filter water to remove microbes and also endotoxins/pyrogens
- Use materials that meet acceptance specifications
343
Endotoxins/pyrogens
- Any substance that when injected leads to a rise in body temperate, can be endogenous (eg IL-1) or exogenous
- Non-infectious
- Most common are produced by gram -ve bacteria (also known as endotoxins)
344
Read ova L27, pg 1
& Method of sterilization/ disinfection
- Heat - dry & moist
- Filtration
- Radiation
345
Heat
L27, pg 2
- Limited by the thermo-stability of the product
| - Can minimize impacts, while still achieving killing, with higher temp for shorter periods of time
346
Dry heat sterilisation
- Direct flaming - loops & needles, heat to glowing red
- Incineraction - denatures everything at 850*C
- Hot air sterilisation
347
Dry heat sterilisation
hot air sterilisation:
- Uses an oven
- 180*C for 60 min or 160*C for 120 mins
- Suitable for glass, metal objects, non-aqueous thermostable liquids, thermostable powders
- Used commonly in hospitals
- In industry for glass bottles for aseptic filling
- Excellent means of inactivating pyrogens/endotoxins = depyrogenation at 250*C for at least 30 min
348
Dry heat sterilisation
- Kills via oxidative damage
- Heat delivered by radiation and convention - have a fan to circulate the hot air
- Cooling time required
- Spores resistant
349
Moist heat sterilisation
L27, pg 3
- Dressing , surgical equipment, fluids
- Commonly 121*C for 15 min plus cooling time
- Reliable and safe
- Uses an autoclave to raise the temperature of the steam , is doubled walled steel jacketed to withstand the increased pressure
- Steam must penetrate into/onto material
- Spores killed at 121*C but prions require 134*C
- Kills via hydrolytic damage (more effective than oxidative)
- Spores - membrane and protein effect but requires higher temperatures
350
Prions & High temperature short time (HTST)
L27, pg 3 & 4
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351
Filtration
L27, pg 4
- Method for removing (does not destroy) microbes and particles by passing a liquid or gas through a fliter
- Used for heat sensitive products and commonly as terminal sterilization method in aseptic dispensing eg fluids, medicines
352
Filtration
Removes particles (live and dead) due to:
- Size - sieving, membrane type filters
- Adsorption to filter matrix - depth type filter
- Can have a number of filters in parallel, both types
353
Filtration
how big is a bacteria
L27, pg 4
- 0.45 um forst used, but then found some smaller bacteria
- then 0.22 (or 0.2 um) = 'sterilising filter'
- But then found smaller bacteria were getting through
- 0.1 um filter
- there is no good evidence 0.1 is any better thjan 0.2 at keeping out small bacteria
- & it increases processing times (slower flow rate) ... so 0.22 um used most commonly
354
Filtration - for viruses
Micro-filtration:
Ultra-filtration:
L27, pg 5
Micro-filtration:
- pore size of 0.1 - 10 um, removes bacteria and some viruses
Ultra-filtration:
- pore size of 0.001-0.1 , complete removal of viruses, removal of pyrogens, commonly use 20 nm
- Usually pre-filter to remove big particulates (0.22 um or 1 um) and reduce filter blockage (caking) and/or can use tangential flow filtration (TFF)
355
Filtration modes
L27, pg 5
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356
Radiation
Advantages:
Disadvantages:
Radiation
Advantages:
- Terminal process - penetrates through packaging materials
- Suitable for temperature sensitive drugs
- No chemicals, no residues
- Flexible - gas, solids, liquids
Disadvantages:
- High set up costs, specialised facilties, disposal of radiation source (gamma radiation)
- Product, material breakdown
357
radiation - gamma rays
- From cobalt 60 contained in a shielded concrete bunker in a water pool
- Source is raised up to concrete shielded sterilisation chamber and materials pass by on a conveyor belt
- Sterilisation time is many hours (around 20)
- Kills via hydroxyl and oxygen radicals - DNA damage
358
Radiation - e-beam
- Electrons generated by accelerators
| - Limited to small packs, minutes to hours
359
radiation - x rays, UV
X-ray:
UV:
radiation - x rays, UV
X-ray:
- For large packages/items
- Hours
UV:
- For surfaces eg biosafety cabinets, laminar flow hood, clean rooms and equipment used in them
- ~30 mins
- Sterilisation or disinfection
360
radiation - summary
L27, pg 6
bhvsvfsd
361
What is rheology?
Why is rheology important in pharmacy?
L28, pg 4
- The science of flow (or deformation)
| - Study of the behaviour of materials under influence of stress
362
Viscosity (n)
=?
Viscosity = resistance of material to flow or movement
363
Classifying flow properties of materials
Newtonian:
Non-newtonian:
Classifying flow properties of materials
Newtonian:
- Flow properties obey Newtons law of flow
Non-newtonian:
- Flow properties do not obey Newtons law of flow
eg emulsions, suspensions, creams, oinments, gels
364
Newtons equation of flow
L28, pg 7 & 8 & 9
- Newtons law of flow states that the rate of flow is directly proportional to the applied stress
365
Units of viscosity
L28, pg 10 & 11
rgbfvedc
366
Newtonian materials
L28, pg 12 & 13 & 14
rvfecd
367
Non-Newtonian materials
L28, pg 15
tgrftgrfe
368
Classification of Non-Newtonian materials
According to type of flow behaviour:
1. Plastic flow
2. Pseudoplastic flow
3. Dilatant flow.
4. Thixotropic flow
369
1. Plastic flow (Bingham bodies):
L28, pg 17 & 18 & 19 & 20
Pg 17 - Materials that do not flow at low shear stresses but flow like Newtonian-liquids above their yield value
Pg 18 - "real plastic materials"
- Slight curvature usually seen below the yield value
Pg 20 - What causes plastic flow?
- Associated w/ the presence of flocculatd particles eg concentrated suspensions
370
2. Pseudoplastic flow
L28, pg 21 & 22 & 23 & 24
pg 21 - Materials whose VISCOSITY DECREASES with an increasing rate of shear stress
pg 22 - Slope of the curve inc. with inc. shear stress -> apparent viscosity dec. with inc. shear stress = shear thinning
371
What causes pseudoplastic flow?
- At rest - interdigitation of long chain polymers cause large internal resistance to flow
- As shear stress inc. the disarranged polymer chains align in the direction of applied shear stress
- Orientation dec. the internal resistance to flow
On removal of shear stress --> immediate reversal of structure
- Maximum apparent viscosity at rest
372
3. Dilatant flow
- Materials whose VISCOSITY INCREASES w/ an increasing rate of shear stress
373
Dilatant flow (shear thickening)
L28, pg 29
- Flow curve passes through origin (no yield value)
| - Slope of flow curve dec with inc. shear stress
374
Dilatant flow
L28, pg 30
- Viscogram for dilatant material (shear thickening)
| - Apparent viscosity inc. with inc. shear stress = shear thickening (contrast to pseudoplastic systems - shear thinning)
375
What causes dilatant flow?
- Suspensions w/ high percentage of dispersed solids
- pastes
- deflocculated suspensions
- System inc. volume when sheared -> dilatant
376
What causes dilatant flow?
At rest:
L28, pg 32
- Particles are closely packed w/ the interparticle volume (or voids) being at a minimum
377
What causes dilatant flow?
Low shear stress:
L28, pg 33
- Particles begin to break apart and distribute in the medium
378
What causes dilatant flow?
High shear stress:
L28, pg 34
- Particles clump together
| - Insufficient liquid (amount of vehicle is constant) to lubricate particles -> resistance to flow inc.
379
Quick quiz
L28, pg 35 & 36
tefcjd
380
Problem with dilatant materials
- Exhibit inc. viscosity with inc shear stress
| - eg in blenders , mills or even in mortar and pestle
381
4. Thixotropic flow
- Materials whose viscosity depends on the DURATION and the RATE OF SHEAR STRESS
382
Thixotropic flow
L28, pg 39 & 40
- Reversible, time-dependent dec. in apparent viscosity
- HYSTERESIS LOOP - curve obtained on inc. shear stress is not superimposable with that obtained on dec. shear stress the system is thixotropic
383
Why is thixotropy useful?
- inc viscosity at rest -> inc. product stability
- Slows the rate of particle sedimentation
- Dec. viscosity w/ mixing --> product remains sufficiently fluid to allow administration of dose after shaking
384
Viscosity modifiers
L28, pg 42
- Cellulose and its derivatives
- Natural gums
- Sodium alginate (extracted seaweed)
- Synthetic polymers
385
Definitions
Sterilisation:
- Process of killing microorganisms, both vegetative and spore forms
- Can be physical or chemical
386
Chemical Sterilisation:
- Gaseous sterilization using ETHEYLENE OXIDE and FORMALDEHYDE
- Kill via alkylation of sulphydryl, amino, hydroxyl and carboxyl groups on proteins and imnio groups of nucleic acids
- Low temperature
- Non-corrosive
- Effective, penetrates well
- Small to large volumes
387
Ethylene oxide - EtO
- Highly explosive, carcinogenic & mutagenic gas
- Need an air tight, explosive resistant chamber
- Penetrates well through packaging but need to allow it to desorbed post-treatment
- Needs water to kill via humidification step
388
Formaldehyde:
- Even more dangerous then EtO
- Again need water
- Low Temperature Steam and Formaldehyde (LTSF) sterilisation
- Cheaper than EtOH, does not penetrate as well
389
Disinfection definition:
- Process of killing microorganisms on/in inanimate objects to an acceptable level , not harmful to human health. Spores not necessarily killed. Are levels of disinfection
390
Antiseptic definition:
Preservative definition:
Antiseptic definition:
- Chemical used to kill (or inhibit the growth of) organisms on/in living tissues, therefore must not be toxic or irritant. Might be the same chemical used for disinfection but at a lower dose
Preservative definition:
- Included in a product to prevent microbial growth (product is not sterile, or sterility may not be maintained in normal use)
- Must be -non-toxic in relation to route of administration of the product
391
Choice of chemical agent
Depends on:
- Microbial contamination - type and amount, resistance, spores (little activity), myobacteria (resistant)
392
Choice of chemical agent
Microbial contamination
- Fungi - good activity both vegetative state and spores
- Viruses - variable, better for enveloped viruses - HIV, HBV, Influenza
- Prions - resistant
Product to be decontaminated
393
Choice of chemical agent
what else is present (blood, tissue, pus)?
- May inhibit activity and penetration - clean first then disinfect
394
Choice of chemical agent
Properties of chemical agent
- Mechanism of action
- Toxicity for personnel when using these for product manufacturer
- Toxicity for consumer
395
Alcohols
- Denature proteins in vegetative microbes, including Myobacteria, not against spores and at 90% active against fungi and envelope viruses
- Poor penetration of organic matter
Disinfectants/Antiseptics
- Ethyl alcohol (ethanol) and isopropyl alcohol at greater than 70-90% in water
Preservatives
- Benzyl alcohol, chlorbutol, phenylethanol - injections and eye drops are 0.25-0.5%
396
Alcohols - skin swabbing pre-injections
- No evidence that it is useful/necessary
| - But patients like to see you do it
397
Aldehydes
- Broad spectrum including spores
- Cross link proteins
- not affected by organic matter, but toxic
vfcrgf
398
Biguanides eg clorhexidine
- Disrupt cell membranes - therefor less active against non-enveloped viruses, myobacteria, gram negative bacteria, fungi
- Not effective against spores
- Useful for surgical scrubm handwashing topical antisepsis for patients before surgery or needle injection, oral rinses
- Generally well tolerated but can cause occasional sensitivities
399
Halogens
- Oxidise cellular components, rapidly kill bacteria, fungi and viruses, and fungi at high concentrations
Chlorine
- Hypochlorite (bleach) - Highly anti-microbial but highly corrosive, inactivated by organic materials, when diluted to working strength is unstable (release of chlorine gas)
Iodine
- Aqueous iodine - Less sensitive to organic matter than chlorine, but stains skin/fabrics
- Povidone-iodine - Slow release of elemental iodine (microbiocidal) from povidine, less toxixity but must stay in contact with skin for 2 minutes
400
Hydrogen peroxide and peroxygen compounds
- Disinfectant and antiseptic, environmentally safe
- Solutions, creams
- Free radicals cause broad spectrum killing - bacteria, fungi, viruses & spores (higher conc, longer times)
- Inactivated by light and enzymes (catalase, peroxidase)
401
Phenols
- Not active against spores, activity reduced by organic matter, denature proteins
- Originally obtained by distillation of coal or petroleum
- Synthetic phenols less active but less toxic antiseptics eg chloroxylenol & triclosan
402
Cationic surface acting agents
- Insert into membranes, active against bacteria (best against gram +ve), enveloped viruses, fungi, not active against spores
- Quaternary ammonium compounds (QACs) - well tolerated, non-toxic
403
Heavy Metals
- Infrequently used now due to concerns w/ toxicity
| - Most recently the organomercury thimerosol was used as a preservative in multi-dose vaccines
404
Combo product - triGene Disinfectant
Contains:
- n-alkyl dimethyl benzyl ammonium chloride
- Didecyl dimethyl ammonium chloride
- Poly (hexamethylene) biguanide hydrochloride
- Dodecylamine
- Advanced nanoparticle formulation & a penetration enhancer
- Non-corrosive
- Bactericidal, viricidal, fungicidal
- Safe and easy to use
405
Soap, Refrigeration, Freezing, Drying
- Not methods for killing microbes
- Soap removes but not kills (cleaning)
- Refrigeration - Not killed, heated back up microbes will grow
- Freezing - get negligible growth and a little killing
- Drying & freezing (lyophilization) - removes water but does not kill
406
Biological Sterilisation
- Not yet but maybe some day
- Safe
- Limited host range
- Already used to disinfect food
407
Preservatives
Properties:
- broad spectrum of anti-microbial activity
- Rapid rate of kill
- Selectivity (does not degrade/inactivate) the drug
- Safe - non-toxic, non-irritant, odor and taste acceptable
- Stable
- Used where is high risk of contamination post-opening - multi-use liquids (including creams & emulsions)
408
Preservation
- No preservatives safe enough for inclusion into ocular or intrathecal medicines
409
Acids and Esters
- Generally found in weak acids, undissociated form is the active antimicrobial, therefore pKa is important in formulation
410
Quality assurance also required of:
- Bioburden of starting materials
- Environmental monitoring
- Validation and in-process monitoring
- As well as end product sterility testing
411
Bioburden
- Must conform with pharmacopoeia specifications
- Levels will impact on sterilisation required, a wrong estimation may result in the choice of an inappropriate process
- Must also know the type of organism - human pathogens, spores, pyrogens, prions?
- Safest approach - assume resistant spores
412
Environmental monitoring
- Air quality & contamination - Settle plates
- Surface contamination - Swabbing & contact plates
- Operator monitoring - gloves & face masks, finger dab plates
... at frequency required by local regulations
413
Settle Plates
- Agar plates which are kept open while manufacturing processes are ongoing or sample a set amount of air
- Use a growth medium with low specificity eg nutrient agar, tryptone soya agar (TSA), blood sugar, Columbia agar
Should be incubated as soon as possible
- 30-35*C for at least 2 days for bacteria
- 20-25*C for at least 5 days for fungi
L30, pg 2
414
Settle plates
Reading plates:
- Count the number of discrete colony forming units (cfu) on each sample
- Even the presence of 1 pathogen will be unsatisfactory
- The microbial deposition rate may be reported as the number depositing in a given area per unit time
415
Finger dab plates & swabbing
To show breakdowns in aseptic technique
Used to evaluate operator training - sample more frequently during training
- touching face/nose
- Touching non-sterile items
- Failure in sterilisation of items
416
Contact Plate
- Have a raised surface
- Direct application to surfaces
- Monitor hygiene control, cleaning
- Swabs
417
Validation and in-process monitoring
Necessary for each stage of the manufacturing process (large or small scale) to ensure quality assurance
Need:
- Detailed protocols
- Appropriate facilities & calibrated equipment
- Training & competence assessment
- Certified testing (equipment & processes) & data analysis
418
Validation and in-process monitoring
A successful validation programme will allow manufacturers to
- Understand the sources of variation
- Detect the presence and degree of variation
- Understand the impact of variation on the process and ultimately on product attributes
- Control the variation in a menner commensurate with the risk it represents to the process and product
- To do this use different types of indicators - physical, chemical, biological
419
Validation of sterility - physical indicators
- Temperature records - chart/digital records
- Gas sterilisation - gas concentration, humidity & pressure records
- Radiation - dosimeter
- Filtration - Pressure differentials, diffusion rates, retention efficiencies
420
Validation of sterility - Chemical indicators
- Based on the process altering the chemical or physical characteristics (colour change or melting) of a chemical
421
Validation of sterility - Biological indicators
- Use bacterial spores to validate sterility
| - Must be non-pathogenic and have above average resistance to the sterilization process
422
Validation of sterility - biological indicators
- placed in dummy packs in the sterilizer
| - Then transferred to medium for growth assessment = sterility test
423
Sterility test
- No one media or set of conditions will support the growth of all bacteria
- Use a media with low selectivity
424
Preservative Testing
- Challenge test in final container w/ Pseudomonas aeruginosa, Staphyloccoccus aureus, Candida albicans, Aspergillus brasiliensis
- Product stored as per normal use and samples taken relating to product life and grown, microbial cfu counted
- Control has no preservative
- Set limits in pharmacopoeia for efficacy in inhibiting microbial growth
425
Pyrogen testing
L30, pg 4
- Rabbit pyrogen test
- Limulus amebocyte lysate (LAL) test - less ethicalcost, sensitive, cheaper, easier but needs fresh reagents
- Now test via ELISHA - monocyte activation test (MAT) or whole blood in vitro pyrogen test (IVPT)
