Exam 1 - Preformulation

Question 1

Drug delivery process:

Answer 1

1. Compound Bank / Library
2. Hits
3. Data Generated (i.e. MOA, SAR, Specificity to receptors, PK, etc.)
4. Leads
5. Data Generated (i.e. mechanism of interaction with protein, required solubility, in vivo data, etc.)
6. Candidates

Question 2

Formulation:

Answer 2

The process of turning a drug candidate into a drug product.

Question 3

Preformulation:

Answer 3

Preformulation is undertaken to determine the physicochemical properties of a drug candidate or potential drug candidate.

Question 4

Preformulation Assay Development:

Answer 4

• Assays should require as little material as possible to perform the test
• Ideally, different tests for different parameters are performed on the same material sample
• Accuracy/precision/reliability good enough for “go/no-go” decisions on advancing a drug candidate

Question 5

Solubility:

Answer 5

• Probably the most important property for “developability” of a NCE (API) into a drug
• Early nonclinical ADME and Safety formulations are typically liquids = solubility >1 mg/mL
• For final oral formulations: solubility >10 mg/mL

Question 6

Solubility dissolution is a phase transition:

Answer 6

• solid-solid & solvent-solvent bonds broken

* solute-solvent bonds formed – i.e. drug molecules become solvated

Question 7

Equilibrium solubility:

Answer 7

• A solution in which the dissolved drug is in equilibrium with an excess of solid drug is considered to be saturated.
• Intrinsic solubility – equilibrium solubility of the unionized form of a drug that possesses an ionizable group

Question 8

Stable polymorph:

Answer 8

has the lowest solubility

Question 9

Metastable forms:

Answer 9

have higher solubilities

Question 10

Amorphous forms:

Answer 10

have highest solubility

Question 11

Determination of Intrinsic Solubility:

Answer 11

• Saturated solutions in 0.1 M HCl; 0.1M NaOH; H2O

• Measured solubilities the same in all three solvents?
• Solubility in acid the highest?
• Solubility in base the highest?

Measured at 4 degrees c, 25 degrees c, 37 degrees c

Question 12

Intrinsic Solubility and Effect of Impurities:

Answer 12

• if the NCE is pure then all sequential amounts of the NCE added to the solvent will dissolve in a linear fashion (1:1) until saturation is reached
• presence of a single impurity will alter this phase-solubility diagram
• Impurities can increase or decrease solubility

Question 13

Molecular Dissociation

Answer 13

• determination of pKa important in reformulation

* allows possibility of manipulation of drug solubility via salt selection

Question 14

Partitioning Between Aqueous and Lipid Environments:

Answer 14

• Solute added to a mixture of equal volumes of two immiscible solvents (e.g. octanol & water)

Question 15

Intrinsic dissolution rate (IDR):

Answer 15

the rate of dissolution of a pure pharmaceutical active ingredient when surface area, stirring speed, pH and ionic-strength of the dissolution medium are kept constant.

Question 16

What does it mean if IDR > 1 mg/cm2/min?

Answer 16

assume unimpeded absorption

Question 17

Intrinsic dissolution rate (IDR) is used for:

Answer 17

1. Evaluation of the drug solubility in accordance to the biopharmaceutical classification system (BCS)
2. Comparison of different forms/salts of the same compound (is a higher dissolution rate obtained by changing salt?)
3. Setting specifications for particles sizes
4. Development of dissolution methods

Question 18

Salt Selection:

Answer 18

• > 50% of available APIs are salt forms
• beneficial or detrimental
• formed by reacting an acid with a base
• compound with a pKa

Question 19

Salt Selection, classes:

Answer 19

• First class salt-formers form physiological or metabolically ubiquitous ions
• Second class salt-formers – not naturally occurring but no significant toxicity (sufonates, mesylates)
• Third class salt-formers – used to solve a special problem; not natural / not in common use.

Question 20

Hygroscopicity:

Answer 20

• tendency of a material to absorb or adsorb water
• affects physicochemical properties:
-powder particles “stick together”
-increase chemical degradation via water-mediated reactions
-crystallization of amorphous material
• require humidity controlled manufacturing / processing and packaging

Question 21

Hygroscopicity “rule of thumb”:

Answer 21

• Leads / candidates after 24 hrs @ 90% RH

* 7% w/w water uptake – should not proceed to development (clavulanic acid / clavulanate K)

Question 22

Physical Form, Polymorph:

Answer 22

• compound can crystallize to more than one crystal form
• Different polymorphs have different physicochemical / biopharmaceutical characteristics (compressibility / bioavailability)
• polymorph screening by x-ray diffraction or DSC
• Amorphous – compounds that can’t easily form large number of distinct crystals – essentially unstable

Question 23

Physical Form, Stable form:

Answer 23

highest melting temperature

Question 24

Physical Form, Metastable forms:

Answer 24

all other forms

Question 25

Powder Properties:

Answer 25

* Critical for processing of pharmaceutical powders * Particle size & shape * Affects powder flow for blending, tableting, & capsule fill

Question 26

Powder flow predicted by:

Answer 26

* angle of repose - steeper the angle, better flow | * bulking tapped density

Question 27

Compaction Properties:

Answer 27

* Result of compression and cohesion properties of a drug * These properties usually not good for most API * Problems overcome via use of excipients

Question 28

Example of excipients:

Answer 28

* dibasic calcium phosphate * methylcellulose * starch * lactose