Exam 1 - Preformulation Flashcards
Drug delivery process:
- Compound Bank / Library
- Hits
- Data Generated (i.e. MOA, SAR, Specificity to receptors, PK, etc.)
- Leads
- Data Generated (i.e. mechanism of interaction with protein, required solubility, in vivo data, etc.)
- Candidates
Formulation:
The process of turning a drug candidate into a drug product.
Preformulation:
Preformulation is undertaken to determine the physicochemical properties of a drug candidate or potential drug candidate.
Preformulation Assay Development:
- 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
Solubility:
- 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
Solubility dissolution is a phase transition:
- solid-solid & solvent-solvent bonds broken
* solute-solvent bonds formed – i.e. drug molecules become solvated
Equilibrium solubility:
- 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
Stable polymorph:
has the lowest solubility
Metastable forms:
have higher solubilities
Amorphous forms:
have highest solubility
Determination of Intrinsic Solubility:
• 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
Intrinsic Solubility and Effect of Impurities:
- 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
Molecular Dissociation
- determination of pKa important in reformulation
* allows possibility of manipulation of drug solubility via salt selection
Partitioning Between Aqueous and Lipid Environments:
• Solute added to a mixture of equal volumes of two immiscible solvents (e.g. octanol & water)
Intrinsic dissolution rate (IDR):
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.
What does it mean if IDR > 1 mg/cm2/min?
assume unimpeded absorption
Intrinsic dissolution rate (IDR) is used for:
- Evaluation of the drug solubility in accordance to the biopharmaceutical classification system (BCS)
- Comparison of different forms/salts of the same compound (is a higher dissolution rate obtained by changing salt?)
- Setting specifications for particles sizes
- Development of dissolution methods
Salt Selection:
- > 50% of available APIs are salt forms
- beneficial or detrimental
- formed by reacting an acid with a base
- compound with a pKa
Salt Selection, classes:
- 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.
Hygroscopicity:
• 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
Hygroscopicity “rule of thumb”:
- Leads / candidates after 24 hrs @ 90% RH
* 7% w/w water uptake – should not proceed to development (clavulanic acid / clavulanate K)
Physical Form, Polymorph:
- 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
Physical Form, Stable form:
highest melting temperature
Physical Form, Metastable forms:
all other forms
Powder Properties:
- Critical for processing of pharmaceutical powders
- Particle size & shape
- Affects powder flow for blending, tableting, & capsule fill
Powder flow predicted by:
- angle of repose - steeper the angle, better flow
* bulking tapped density
Compaction Properties:
- Result of compression and cohesion properties of a drug
- These properties usually not good for most API
- Problems overcome via use of excipients
Example of excipients:
- dibasic calcium phosphate
- methylcellulose
- starch
- lactose
