Preformulations Review questions

Question 1

Define preformulation

Answer 1

preformulation = physicochmeical characterization of the solid and solution properties of compounds prior to dosage for development

characterization falls into interinsic and derived properties

intrinsic: inherent to the molecule, can only be affected by chemical mofidications
derived: related to intermolecular interactions, can be affected by the physical shape, environment and solid state form

Question 2

what the the purpose of preformulation

Answer 2

1. identifying the deasibility of possile dosage forms for the new drug
2. guide to the suitability of various excipients to be used in formulation
3. predicting any potential formultion problems (ex stability issues or poor bioavailability)

Question 3

scope of preformulation studies

Answer 3

• depends on factors like:
  company: some companies want super detailed, some only do the abre minimum

Question 4

When, during drug development, preformulation takes place?

Answer 4

if drug shows potenti pharmacological effect in vitro and animals will move forward to preformulation studies

Question 6

List the most important physicochemical tests conducted during preformulation

Answer 6

1. Chemical identity and purity tests -> developing analytical methods
2. Solution properties: solubility, pKa, logP, dissolution, salt forms, stability
3. Solid state properties: crystal structure, polymorphism, hygroscopicity, stability, crystal habit, particle size, powder flow properties (later stages), excipient compatibility

Question 7

what are the two mandatory fundamental solubiltiy parameters to be determined for an NCE

Answer 7

intrinsic solubility C₀: fundamental solubility when the drug is unionized

Dissociation constant pKa: ionization o weak bases and weak acids at diff pH

Question 8

what is solubility

Answer 8

• max amount of drug that can be dissolved in a fixed amount of solvent at a specific temp
• at equilibrium this is called a saturated solution
• usually the frist paramer measured in drug performulation (esp impo is the aqueous solubility

Question 9

What are the specific solubility considerations for a new compound?

Answer 9

1. Aqueous solubility: if <1% (10mg/mL) over pH range 1-7 at 37 C may have bioabs problems
2. Solubility less than 1 mg/mL indicates need for a salt, esp if tab/caps

*range of 1-10mg/mL seriously consider salt formation

*if drug cannot be manipulated this way (neutral mol like glycosides, steroids or alc or where pKa is less than 3 for a base or greater than 10 for an acid) liquid filling in soft/hard gel caps may be req

Question 11

What are the ways to increase solubility of an NCE?

Answer 11

1. Salt formation
2. Use of solvents / cosolvents

• oils
• non aq water miscible pharmaceutically acceptable solvents
• organic solvents for analysis

*common ion effects solubility, will have dec solubility in presence of common ion (dec solubility HCl salt in gastric juice)

*use salt forms: tosylate, mesylate, napsylate, besylate, maleate (decreasing acidity)

*if low solubility amine drugs use salts of polyhydroxy acids eg. lactate

Question 12

What is involved in salt selection and what are the specific consideration when selecting salt forms for an NCE?

Answer 12

1. Dosage form considerations
   
   • IV vs oral
   • high vs low dose
   • excipient compatability
   • interaction w/ other actives in potential combination formulations
2. Salts and other solubilization technies
   
   • effect of salts on complexation binding constants
   • effect on solubilization by surfactants
   • solubility of salts in non aq solvents
3. Toxicological considerations

Question 13

Define intrinsic solubility and intrinsic dissolution rate.

Answer 13

Intrinsic solubility (C₀) – fundamental solubility when the drug is unionized Intrinsic dissolution rate: when dissolution rate is solely controlled by diffusion

Question 14

What is pKa and how is it used to influence solubility of drugs?

Answer 14

Dissociation constant (pKa): ionization of WB and WA at different pH

*allows the informed use of pH to maintain solubility and choose salts required to acheive good bioavailability from the solid state and improve stability and power properties

Question 15

Define partition coefficient and log P.

if log P = 3, what does this mean?

Answer 15

Partition coefficent Ko/w and log P – a measure of lipophilicity

P_o/w = C_organic/Caq phase

LogP = tabulated value to indicate lipophilicity

LogP=0 compound is equally soluble in water and octanol

logP=5 comp is 100,000x more soluble in octanol

logP=-2 drug 100x mroe soluble in water

Question 16

What is the difference between solubility and dissolution?

Answer 16

Solubility is the amount of drug dissolved in the fluid of interest.
Dissolution rate is the time it takes for the drug to dissolve in the fluids at the absorption site (described by the Noyes-Whitney equation).

Question 17

Solid state properties of drugs include polymorphism, pseudopolymorphism and crystal purity – What are the differences between these?

Answer 17

• Polymorphism = ability of a substance to exist in more than one solid state form
• Pseudopolymorphism (solvates) = solvents in the crystalline lattice lead to change in crystal habit
• Crystal purity refers to the fact that early samples of a new drug are inevitably ‘dirty’ while improvements in synthetic route are made. Thermal analysis can be used as a rapid method and will discriminate 0.002 mole% of impurity.

Question 18

Compare the properties of different polymorphic forms of a drug

Answer 18

• Polymorphic forms of the drug may have differences in some or all of the physical- chemical properties
  * ONLY ONE polymorphic form of the new compound will be thermodynamically most stable
• Metastable polymorphic forms result when bond length and/or bond angles of atoms in the crystal lattice differ from those of the stable form.

Question 19

Generally, the stable polymorph is _____ soluble.

Answer 19

less

Question 20

Compare crystalline and amorphous structures and their significance in solubility and stability

Answer 20

Crystaline

• different molecular packing arrangements in the crystal lattice -> polymorphs.
• diff polymorphs can be prepared by manipulation of conditions of particle formation during crystalization (solvent, temp, rate of cooling)
• only one form of drug is stable at given temp and pressure, others are metastable (convert at diff rates to stable crystaline form)
• most stable has lowest free energy, and possesses highest MP
• some products have more soluble but less stable polymorph, but its stable enoough to survive the approved storage conditions/shelf life, may get crystal regrowth

Amorphous:

• non crystaline materials, posses so long range order
• thermodynamically unstable, in more energetic form
• want to revert to more stable form esp if in aq suspension, often less chemcially stable

Question 21

What are four common drug degradation pathways?

Answer 21

Hydrolysis

b. Oxidation
c. Photolysis
d. Trace metal catalysis

Question 22

Define hygroscopic, deliquescent and efflorescent properties of solids.

What is the relevance to relative humidity of the manufacturing environment? How can you protect the drug?

Answer 22

Hygroscopic: absorb moisture from environment

Deliquescent: Absorb enough moisture to dissolve themselves

Efflorescent: lose water to form lower hydrtae

*must consider relative humidity, pharmaceutial air conditionsing set below 50%, but relative humididty is 55% in temperate climate or 87% in tropics

to protect: Good packaging (glass bottles, foil blisters, desiccants

* In preformulation determine the best excipient combinations, cheapest choice of packaging to reduce hydrolytic instability

Question 23

What are the four main areas of solid state characterization for drug powders during preformulation?

In the design of which dosage forms these parameters are essential?

Answer 23

• Crystal morphology
• Particle size
• Powder flow properties
  
  • Bulk density (Carr’s index)
  • Angle of repose (θ)
  • Compression properties (elasticity, plasticity, fragmentation, punch filming propensity)
• Excipient compatibility

Question 24

Define crystal habit and why is it important to know?

Answer 24

Crystal morphology or habit influence many properties of the compound

* powder flow properties, compaction and stability have all been found to be dependent on crystal morphology.

Question 25

Particle size is a crucial parameter for many reasons. Name at least three reasons in context of dosage form design during preformulation.

Answer 25

*has effect on dose uniformity and dissolution rate

small particles are important when:

Low doses needed

using high potency drugs (small particels for homogeneity)

using drugs with poor sq solubility (<1mg/mL) as dissolution rate is directly proportional to SA

• particel size determiantion (microscope)

Question 26

What are the diff water to decribe particle size according to USP

Answer 26

Feret’s diameter: dist between imaginary parallel lines tangent to randomly oriented particle and perp to ocular scale

martins: diameter or particle at point that divides particle into two equal projected areas

projected area diameter: diameter of a circle that has same projected area as the particle

length: longest dimension from edge to edge
width: longest dimension of particle measured at aright angles to the length

Question 27

What are the different ways to measure and present particle size distribution? What is meant by monodisperse and polydisperse particle populations?

Answer 27

Particle size can be assessed by microscopy and dynamic light scattering.

Monodisperse particle population would include particles with all the same size, however, this does not exist in real situations, since there is always a certain distribution of sizes exist, this is called polydispersity.

Question 28

What are the important powder flow properties for tablet and capsule formulations?

Answer 28

• Bulk density (Carr’s index
• Angle of repose (θ)
• Compression properties (elasticity, plasticity, fragmentation, punch filming propensity)

Question 29

Define Carr’s index and angle of repose and what it is used for?

Answer 29

The increase in bulk density of a powder is related to the cohesivity of a powder.
Carr’s index: Ratio of the poured to tapped bulk densities are expressed to give indices of flowability

Question 30

What is the most common method used to evaluate excipient compatibility?

Answer 30

Thermal analysis, eg DSC (differential scanning calorimetry)

Question 31

How bioavailability and preformulation related?

Answer 31

Bioavailability = rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action

Preformulation deals with the characterization of the new drugs properties that directly affect its bioavailability such as solubility, dissolution, pKa and solid state properties.