Dosage Forms & Delivery Systems

Question 1

Solubility of Drug in its salt is a function of

Answer 1

PH

Question 2

Characteristics of a drug’s salt form to consider

Answer 2

Acceptable organoleptic properties
Good flow and compaction properties
Minimal hydration
Non-hygroscopic properties
Non-polymorphic properties
Non-toxic
Reproducible particle size
Stability
Suitable aqueous solubility and intrinsic dissolution
Suitable and sharp melting point

Question 3

Organoleptic properties determined by

Answer 3

Visual Inspection» Product description

Question 4

Liquid state in solid formulations

Answer 4

Facilitates the homogeneous dispersion of a drug into a base.

Question 5

Advantages of Capsule

Answer 5

> Easy to administer; well accepted by adults
> Easy to prepare but it takes practice
> Hides taste
> Good stability when dry
> Accommodates multiple ingredients

Question 6

Disadvantages of Capsule

Answer 6

> Fixed dose; cannot break open capsule
Dosage adjustments are problematic
Hard to make correctly; technique-dependent
Blending without testing; all technique
Hard to acquire uniform fill weights
Subject to moisture retention
Can be difficult to swallow

Question 7

The Goldilocks Principle - Capsules

Answer 7

Too much water or too little water can be problematic.

Question 8

Efflorescence

Answer 8

is the change to a powder from loss of water or crystallization.
Risk: The weight of the powder is less than what it should be, and thus may contain a greater amount of drug for a given amount of powder.

Question 9

Hygroscopicity

Answer 9

is the ability to absorb moisture in the air

Question 10

Deliquescence

Answer 10

s the ability to take on water molecules from the surrounding and eventually liquefy.

Question 11

Risks with Hygroscopicity and Deliquescence

Answer 11

In either case, there can be melting or dissolution because of exposure to water in the air.

The gaining of water, or wetting, results in the weight of the powder being greater than what it should be. It may now contain a lesser amount of the drug because it is diluted by newly gained water

Question 12

Strategies to maintain the integrity of Powders and Powder-filled Capsules

Answer 12

> Use airtight containers
Immediately close the container lid after weighing a powder
Limit shelf time
Protect from light
Add a chelating agent; ex: EDTA prevents oxidation by metal ions
Add an antioxidant; ex: Vitamin E, Vitamin C, CoQ10, or BHT
Store in a cool and dry environment
Control storage temperature
Control pH

Question 13

Efflorescent Powders

Answer 13

Alums
Atropine sulfate
Caffeine
Calcium lactate
Citric acid
Cocaine
Codeine
Codeine phosphate
Codeine sulfate
Ferrous sulfate
Morphine acetate
Quinine bisulfate
Quinine hydrobromide
Quinine hydrochloride
Scopolamine hydrobromide
Sodium acetate
Sodium carbonate
Strychnine sulfate
Terpin hydrate

Question 14

Hygroscopic

Answer 14

Ammonium bromide
Ammonium chloride
Ammonium iodide
Calcium bromide
Calcium chloride
Ephedrine sulfate
Hydrastine hydrochloride
Hydrastine sulfate
Hyoscyamine hydrobromide
Hyoscyamine sulfate
Iron and ammonium citrate
Lithium bromide

Question 15

Deliquescent Powders

Answer 15

Pepsin
Phenobarbital sodium
Physostigmine hydrobromide
Physostigmine hydrochloride
Physostigmine sulfate
Pilocarpine alkaloid
Potassium acetate
Potassium citrate
Sodium bromide
Sodium chloride
Zinc chloride
Lithium bromide

Question 16

Capsule delivery route

Answer 16

Capsules have applications in the delivery of oral medications, as well as the delivery of accurately measured rectal and vaginal medications

Question 17

Capsule used when

Answer 17

Capsules are used when a patient has difficulty swallowing a tablet or when there is a need to combine two or more medications.

Question 18

Hard-gelatin capsules comprised of

Answer 18

gelatin, sugar, and water, with or without a dye and/or opacifying agent or sulphur dioxide preventing its decomposition.

Question 19

Capsule size selection

Answer 19

should be just slightly greater in volume capacity than the powder itself

Question 20

The best capsule type for powder fills are

Answer 20

‘locking’ capsules that, once closed, are difficult to reopen.

Question 21

Hard-gelatin capsules are composed of

Answer 21

13% to 16% moisture and they can absorb ten times their weight in water

Question 22

Diluents are added to the powder-fill in capsules to

Answer 22

> increase bulk volume to a reasonable volume.

> sometimes used to offset the rate of release of the drug.

Question 23

Parts of a Capsule

Answer 23

A capsule has two parts: a body (or base) and a cap.

Question 24

Capsule body is

Answer 24

the narrower of the two parts and is what is filled when the drugs and excipients are added to the capsule.

Question 25

Capsule cap is

Answer 25

the wider and shorter of the two parts and fits over the body to close the capsule.

Question 26

Capsule Storage consideration

Answer 26

To ensure their quality, capsule shells should be stored in an environment where the relative humidity is between 30% and 45% at room temperature.

Question 27

Capsule time to dissolve in the stomach

Answer 27

Capsules dissolve in the stomach within ten to twenty minutes

Question 28

When are capsules not appropriate

Answer 28

> drugs are very soluble, as they may irritate the gastrointestinal lining of the stomach. Salts, such as potassium chloride, potassium bromide, and ammonium chloride, undergo rapid dissolution upon penetration of gastric fluids resulting in a highly concentrated solution.

> Efflorescent materials cause capsular softening when water is lost; deliquescent powders cause capsular hardening when moisture is extracted from within the capsule and into the powder.

Question 29

Required capsule size can be determined using two steps.

Answer 29

The first step is to determine the weight of the drug along with any excipients to be added to an individual dose.

The second step is to determine the volume of this dose.

Once the capsule size is determined, packing statistics are required.

Question 30

Packing statistics

Answer 30

tell you the weight of a chemical at a 100% fill per capsule shell volume.

Question 31

When adding drug from commercial tablets to a capsule

Answer 31

the tablet must be finely comminuted into a powder before it can be used in the capsule.
Only standard release tablets are acceptable for this procedure.

Question 32

Cleaning capsules to remove excess powder from the external capsule by

Answer 32

The first method consists of rolling the closed capsules between the folded surfaces of a dry cloth or shaking them inside a plastic bag lined with a dry cloth.

The second method consists of placing the closed capsules inside a zip-lock bag partially filled with sodium bicarbonate, sugar, or salt, and then gently shaking the sealed bag. The contents of the bag (i.e., the capsules and the sodium bicarbonate, sugar, or salt) can then be separated using a ten-mesh sieve. Salt is the preferred agent.

Question 33

Semi-solid or liquid preparation in a capsule content

Answer 33

the mixture should not contain water.
Water will dissolve the capsule.

Alcohol, fixed oils, and volatile oils could be used since they will not solubilize the gelatin in the capsule

Question 34

Capsules with a Semi-Solid or Liquid Fill steps

Answer 34

> The fill should be prepared as if it were to be administered without capsules.
semi-solid or liquid can be placed in each capsule with the aid of a micropipette, calibrated dropper, or automated technology.
The cap portion of the capsules can now be put in place. There is no immediate need to clean the external surface of the capsules.
it is important to let the capsules lie out for a time and observe them for signs of leakage. Specialized capsules with a double locking mechanism exists for liquid filed capsules.
In the absence of specialized capsules, just prior to recapping the capsule shells, a vinegar solution can be dabbed onto the tops of the shell bodies, and then the caps put in place. This will help seal the shells and aid in the prevention. Prior to using vinegar in this way, the compatibility between the drug and vinegar must be determined

Question 35

Capsules with a Solid Fill steps

• If sufficient plasticity.

Answer 35

> the solid in question is rolled out so that its diameter is slightly narrower than the diameter of the selected capsule size.
The solid roll is then sectioned and separated.
The length of each section must also be shorter than the capsule length.
Each section should weigh the appropriate amount to represent one dose.
Weighing the solid with or without the capsule is acceptable as long as the measurement technique used to calculate the dose weight accounts for the weight of the capsule.

Question 36

Capsules with a Solid Fill steps

• If too high level of plasticity.

Answer 36

> the solid may be melted down to a liquid;
the capsules filled, and allowed to re-solidify.
the melting point of the solid must be lower than that of the capsules. If it is not, the capsule will melt and deform when filled.
The cap portion of the capsule is put in place only after the re-solidification process is complete and the solid is at room temperature.

Question 37

Slow Release Capsules is achieved by

Answer 37

> The use of specialized excipients can be used to alter the rate of release of a drug directly affecting its bioavailability.

Question 38

Slow Release Capsules considerations

Answer 38

> Content uniformity of the powder blend is now increasingly important and patient monitoring required.

Question 39

Slow Release Capsules ingredients

Answer 39

> An agent widely used to manipulate release rate is Hydroxypropylmethylcellulose (HPMC).

> Other agents include Methocel E4M and Hypromellose 2910

Question 40

Hydroxypropylmethylcellulose (HPMC) chracteristics

Answer 40

> It is non-ionic, which means that it has minimal interaction with acidic, basic, or electrolytic systems and it works well with soluble and insoluble drugs at high and low concentrations.

Question 41

Compounding Controlled release (CR) capsules

Answer 41

cannot be compounded as you cannot prove controlled release.

Question 42

Important facts related to slow release capsule include:

Answer 42

> The slow release agent can make up 30%-70% of the powder fill volume.
The ideal amount of slow release agent is 30%–40% of the powder fill volume.
Higher concentrations of slow release agents will decrease temperature required for gelling.
Gel is formed with hydration and heat; it liquefies with cooling.
If data is not available on the quantity of the slow release agent required for a given powder blend, then 50% is a good place to start. While the release rate can be slowed down, a twenty-four (24) hour release rate will not be achieved.
Factors affecting rate of release include pH and rate of hydration of the Methocel type agent.
As the concentration of the release agent in the blend increases, the temperature required for jellification is lower.

Question 43

Types of Tablets

Answer 43

> Chewable
Effervescent
Sublingual and Buccal
Rapid Dissolve Tablets

Question 44

Chewable tablet content

Answer 44

> a disintegrant is rarely needed.
The diluent of choice is mannitol.
Flavoring agents are often included in the formulation.

*Chewable tablets may sometimes be replaced by gum (e.g., Fentanyl gum)

Question 45

Effervescent Tablet content

Answer 45

Effervescent tablets are formulated by the addition of citric or tartaric acid, and sodium or potassium bicarbonate. When mixed with cold water just prior to administration, the acid and bicarbonate react to form carbon dioxide, which provides effervescence and rapid disintegration. Effervescence increases palatability.

Question 46

Sublingual and Buccal

Answer 46

Sublingual or buccal tablets should not contain a disintegrant and should not undergo disintegration in the mouth. While rapid dissolution of the drug is essential, other excipients in the mix do not have to be freely soluble in water. Absorption of the drug occurs directly into the circulatory system bypassing the first-pass effect.

Question 47

Rapid Dissolve Tablets characteristics

Answer 47

> is a solid dosage form
dissolves or disintegrates quickly in the oral cavity
goes into solution or suspension with saliva as the solvent
does not need to be taken with water

Question 48

Rapid Dissolve Tablets used when

Answer 48

Difficulty in swallowing (i.e., dysphagia) is common among all age groups, especially in the elderly, and is also seen in swallowing conventional tablets and capsules (Lindgren S et al, 1993). One study showed that 26% of 1576 patients experienced difficulty in swallowing tablets. The most common complaint was tablet size, followed by surface, form, and taste. The problem with swallowing tablets was more evident in geriatric and pediatric patients, as well as travelling patients who may not have ready access to water (Anderson, O et al, 1995).

Rapid dissolve tablets have a wide range of applications (e.g., neuroleptics, cardiovascular drugs, analgesics, antihistamines, and drugs for erectile dysfunction). (Gupta A et al, 2010).

Question 49

Advantages of Rapid Dissolve Tablets

Answer 49

Ease of administration to patients who cannot swallow16

No need for water to swallow the tablet

Convenience of administration and accurate dosing as compared to liquid formulations

Dissolution and absorption of drug is fast, offering rapid onset of action

Bioavailability of drugs is increased as some drugs are absorbed in mouth, pharynx and esophagus through saliva passing down into the stomach

First pass metabolism is reduced, thus offering improved bioavailability, and reduced dose requirements and side effects

Question 50

Examples of patients who cannot swallow include

Answer 50

the elderly, stroke victims and bedridden patients; patients affected by renal failure; and patients who refuse to swallow (e.g., pediatric, geriatric and psychiatric patients)

Question 51

Requirements of Rapid Dissolve Tablets

Answer 51

Require no water for oral administration, yet dissolve, disperse, and/or disintegrate in mouth in a matter of seconds
Have a pleasing feel in the mouth
Have an acceptable taste masking property
Be harder and less friable
Leave minimal, or no residue, in the mouth after administration
Exhibit low sensitivity to environmental conditions (e.g., temperature and humidity)
Allow for the compounding of the tablet using conventional processing and packaging

Question 52

Ingredients in Rapid Dissolve Tablets

Answer 52

Ingredients used in the formulation of RDTs should allow for quick release of the drug, resulting in faster dissolution. This includes the APIs and excipients. Disintegration and solubilisation of the RDT is dependant upon the effects brought about by the disintegrant, water-soluble excipients, and effervescent agents (Kaur T et al, 2010).

Disintegrants play a major role in the disintegration and dissolution of RDTs. It is essential to choose a suitable disintegrant, at an optimum concentration, to ensure quick disintegration and a high dissolution rates (Kaur T et al, 2010).

Sugar-based excipients are used for taste, taste masking, and as a bulking agents. Taste masking is essential due to an API’s unpleasant and bitter taste. Sorbitol, mannitol, xylitol, dextrose, and fructose make up some of the sugar-based excipients. The aqueous solubility and sweetness of these excipients impart a pleasing mouth feel and offer good taste masking (Kaur T et al, 2010).

Other ingredients commonly used in RDTs include water-soluble diluents, lubricants, antistatic agents, plasticizers, binders, colors, and flavors.

Question 53

Method of Preparation of Rapid Dissolve Tablets

Answer 53

Rapid dissolve tablets are prepared by pressing a sieved homogenous powder blend into a mold and gently heating the tablets in a convection oven. After this procedure, the tablets are tapped out of the mold, cooled, and packaged in blister packs.

Molded tablets have a somewhat porous structure facilitating rapid disintegration and easy dissolution, however, they often times lack sufficient mechanical strength to maintain their structural integrity during handling. The addition of sucrose, acacia, or polyvinyl pyrrolidone can increase this mechanical strength (Kaur T et al, 2010).

Hard and large tablets require more disintegration time, whereas, soft and small tablets have a low mechanical strength. An optimum balance is required to achieve a quick disintegration (i.e., less than 30 seconds) and a high dissolution rate (Watanabe Y et al, 1995).