Pre-formulation Considerations, Hydrates and Solvates & Mechanisms of Drug Degredation

master formula

the formulation that best meets the goals for the product is selected to be its ___

physical description

the purity of the chemical substance substance is essential for its identification and for evaluation of its chemical, physical and biological properties

chemical property

• structure

• form

• reactivity

physical property

• physical description

• particle size

• crystalline structure

• melting point

• solubility

biological property

ability to get to a site of action and elicit response

microscopic examination

• Gives an indication of particle size and size range of the raw materials along with the crystal structure

• Spherical and oval powders flow more easily than needle shaped powders

heat vaporization

• The amount of heat absorbed when 1g of liquid vaporizes

• Operation of implantable pumps delivering medicine

• Aerosol dosage forms

• Nasal inhalants for treating nasal decongestion

• Particle size affects vapor pressure; the smaller the particle size the greater the vapor pressure

melting point depression

• used to determine the purity of the substance

• change in __ means the product is not pure

phase rule

is a useful device for relating the effect of the least number of independent variables upon the various phases that can exist in an equilibrium system containing a number of components.

particle size

• Certain physical and chemical properties of drug substances, including dissolution rate, bioavailability, content uniformity, taste, texture, color and stability are affected by the __ distribution

• flow characteristics and sedimentation rates

• influences oral absorption

polymorphism

• crystal or amorphous

• affects melting point and solubility

solubility

• Should possess aqueous __ for therapeutic effect

• Salt and ester forms is frequently added to increase ___

• Adjustment in particle size and pH can increase ___

dissolution

rate-limiting step in the absorption process

dissolution rate

the time it takes for the drug to dissolved in the fluids at the absorption site

membrane permeability

To produce biological response, the drug molecules must first cross the biologic membrane (acts as lipid barrier) permits absorption of lipid soluble substance by passive diffusion

partition coefficient

measure of drug’s lipophilic character

pK_a / disassociation constant

• The extent of dissociation and ionization of the drug.

• Extent of ionization has strong effect on drugs absorption, distribution, and elimination

hygroscopic powder

tends to absorb moisture from air

deliquescent powder

absorb moisture from air then liquefy

efflorescent powder

give up water of crystallization and may even become damp and pasty

organic salt consideration

drugs are either weak acids or weak bases and have limited water solubility, often used the salts of the product to increase the aqueous solubility

organic ester consideration

Prepared for increase solubility, stability, resistance to degradation after administration, use of prodrug

preformulation stability studies

• solid state stability of the drug alone

• solution phase stability

• stability in the presence of expected excipients

hydrolysis

• A solvolysis process in which drug interact with water to yield breakdown products of different chemical constitution

• Example: Acetylsalicylic acid + water salicylic → acid + acetic acid

• Amides, lactones, and lactams are also prone to hydrolytic decomposition

oxidation

• Involves the loss of electrons from an atom or a molecule

• Common to aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats and oils

stability

defined as the extent to which a product retains, within specified limits, and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of its manufacture

chemical
physical
microbiologic
therapeutic
toxicologic

five types of chemical stability

chemcal

• Each active ingredient retain its chemical integrity and labeled potency, within specified limits.

  • Selecting storage condition (temperature, light, humidity)

  • Selecting the proper container (glass vs plastic; clear vs amber)

  • Anticipating interactions when mixing drugs

physical

The original __ properties, including appearance, palatability, uniformity, dissolution and suspendability are retained

microbiologic

• Sterility or resistance to microbial growth is retained

• Antimicrobial agents that are present retain effective within specified limits

therapeutic

the therapeutic effect remain unchanged

toxicologic

no significant increase in toxicity occur

sodium sulfite

high pH (aqueous prep)

sodium bisulfite

immediate pH (aqueous prep)

hypophosphorous acid and ascorbic acid

low pH (aqueous prep)

oleagenous prep

• alpha-tocopherol

• butyl hydoxy anisole

• ascrobyl palmitate

factors that affects oxidation

• Oxygen present as airspace within the container - nitrogen

• trace elements in drugs, solvent, container and stopper - chelating agent eg. EDTA (EthyleneDiamineTetraAcetic acid) and calcium disodium edetate

• Light - light resistance or opaque plastic

• Temperature - cool place

• pH of the preparation - maintain solution in pH most favorable to its stability