Preformulation and Stability

Learning Objectives:

  • demonstrate the science of preformulation

  • be familiar with the physical and chemical properties that are investigated during preformulation

  • demonstrate the science of drug stability

  • compare physical instability vs. chemical instability

  • know the approaches to prevent the different mechanism of instability

Preformulation

  • preformulation: investigation of physical and chemical properties of a new drug substance alone or in combination with other excipients

  • also a phase of research and development where scientist characterize physical, chemical, and mechanical aspects of a new drug under investigation to develop a stable, safe, and effective dosage form for clinical use

  • during the lead API optimization phase of drug development

  • objective: to increase drug stability, to improve drug bioavailability, to reduce drug/excipient incompatibility

Physical Properties

  • include physical description, particle size, crystalline structure, melting point, and solubility

Physical Description

  • drugs can be used therapeutically as solids, liquids, and gases

    • liquids are less common than solids

    • gasses are the least common

  • liquid drugs

    • problems

      • many are volatile and must be physically sealed from the atmosphere to prevent evaporation lost

        • may be sealed in soft gelatin capsules

      • liquids intended for oral administration cannot generally be formulated into tablet form without chemical modification

        • liquid may be developed into a solid ester or salt form that will be suitable for tablets for drug capsules

    • advantages (those taken in large doses or topically):

      • formulation and stability difficulties are less frequent than solid dosage forms

Heat of Vaporization

  • amount of heat absorbed when 1g of drug substance vaporizes

  • vapor pressure is important for implantable pumps delivering medications as well as in aerosol dosage forms

    • movement of molecules varies with temperature

      • in liquids → molecules escape from liquid into gaseous environment

      • in solid → movement of molecules from solid to vapor state

    • smaller size, the grater the vapor pressure

Purity

  • percentage of specified compound or element in an impure sample

  • usually expressed as a % (m/m) or (W/W)

  • impacts drug stability, appearance, and can be toxic

  • can be detected through:

    • melting point measurement

      • melting/freezing point: temperature at which the pure liquid and solid exist in equilibrium

      • an altered peak or peak at a different temperature → contaminated or impure drug

    • thermal analysis

      • differential scanning calorimeters (DSC): measures temperatures and heat flows associated with thermal transitions in a material

      • thermo gravimetric analysis (TGA): measures weight changes in a material as a function of temperature or time

      • useful in the impurity is water or other residual solvent

    • chromatographic technique

      • preparation of stationary phase and mobile phase

      • thin layer chromatography and high performance liquid chromatography

Microscopic Examination

  • gives information of the particle size, size range, and crystal structure of the raw material

  • for certain processing procedures, the solid drug powders must flow freely and not become entangled

    • spherical and oval powders flow easier than needle-shaped powders

Particle Size

  • impact mose physical and chemical properties

Polymorphism

  • ability of a solid material to exist in more than one form of crystal structure

  • usually exhibit different physicochemical properties including melting point and solubility

  • relatively common in drugs and at least 1/3 of organic compounds

  • a compound that is amorphous will always be more soluble than the crystal form

  • changes in crystal characteristics can influence bioavailability and chemical and physical stability and can impact dosage form processes

  • techniques used:

    • hot stage microscopy, thermal analysis, infrared spectroscopy, X-ray diffraction

Incompatibility with Excipient

  • result of prescribing or mixing of substance which form an undesirable product

Physical Incompatibility

  • mixing of two substances impacts its physical properties (ex: solubility, appearance, miscibility)

  • corrected by: changing solvent, mixing order, or adding a surfactant

Chemical Incompatibility

  • includes chemical reactions such as:

    • reduction

    • oxidation

    • hydrolysis

  • can cause effervescence, color change

Solubility

  • for a drug to enter the systemic circulation and exert a therapeutic effect, it must be first in solution

  • poor solubility = incomplete or erratic absorption

  • to increase drug solubility:

    • chemical modification

    • decrease particle size

    • adjust pH

    • adding cosolvent

    • form complex (ex: cyclodextrin)

  • normally considered a physicochemical constant

    • for weak acids and bases, solubility is pH dependent

Dissolution

  • dissolution rate: time it takes for the drug to dissolve in the fluid

    • if dissolution rate is the limiting step, anything that affects it impacts absorption

    • can impact onset, intensity, and the duration of response, and overall bioavailability

    • can be increased by decreasing drug particle size

    • most effective way to increase = using a highly water-soluble salt of the parent substance

Stability

  • uniformity of a dose and its AI over time must be ensured

  • AI must be available to the patient throughout the expected shelf life of the preparation

Importance

  • harmful events can occur such as:

    • decrease in therapeutic activity

    • degradation of active ingredients and excipients may produce toxic substances

    • physical appearance:

      • settling and caking in suspensions/creaming and separation in emulsions = product unusable

    • tablets may harden or soften

    • creams and other products may discolor

Defining Stability

  • chemical: each AI retains its chemical integrity and labeled potency within specified limits and be uniform dose to dose

  • physical: original physical porperties are retained

    • includes appearance, palatability, uniformity, dissolution, and suspendability

  • microbiological

    • sterile products must maintain sterility

    • non-sterile products must remain free of objectionable microorganisms

    • preservatives must sustain effectiveness within specified limits

  • therapeutic: must remain unchange

  • toxicological: no significant increase in toxicity

Chemical Instability

Oxidation

  • destruction of main type drugs

    • aldehydes, alcohols, phenols, sugars, alkaloids, and unsaturated fats/oils

  • loss of an electron causing a positive valence change

    • oxygen joins durg molecule → free radical → destruction

  • inhibited by:

    • incorporating anti-oxidants and chelating agents

    • avoiding product contact with light which acts as a catalyst

Hydrolysis

  • most common destructive process

  • drug molecules interact with water molecules to yield breakdown products

  • major cause of decomposition because

    • large number of medicinal agents are esters or have amids, lactones, and lactams

  • inhibited by:

    • decreasing amount of water present in product

    • decreasing products exposure to environment

    • controlling pH

Photolysis

  • decomposition by light

  • prevented by:

    • suitable packing in amber colored bottles

    • cardboard outers

    • aluminum foil over wraps

Other Pathways

  • decarboxylation → loss of a carboxyl group

  • racemization → change in steric form

Physical Instability

  • polymorphs: cause variation in solubility, compression, and melting point

  • crystallization: alter size distribution of particles in suspension and usually caused by temperature fluctuations

  • precipitation: formation of precipitates

  • vaporization: loss of solvent which increases conc. and tends happen at higher temperature

  • adsorption: to containers, filters, tubing, syringes, and causes loss of AI which is important for low drug doses


  • protein-based drugs → may lose activity with changes in superstructure

Other Stability Factors

  • temperature

    • increases rates of chemical reactions

  • pH

    • specific acid and base catalysis

    • rates of reaction can vary with pH and large variations are possible

  • light

    • can increase the rate of some chemical reactions

  • air

    • can induce degradation by oxidation

  • humidity

    • decreases stability for drugs susceptible to hydrolysis

    • can accelerate the aging process through reactions with excipients

  • solvent

    • reactions involving ions of opposite charge are accelerated by solvents of low dielectric constant

  • particle size

    • smaller particle size = greater reactivity

    • must be balanced with other formulation factors that are impacted by particle size

  • ionic strength

Microbiological Stability

  • microbiological stability: the formulation has not suffered from any microbiological attack and is meeting the standards with respect to lack of contamination/sterility

  • microbiological contamination can be prevent by preservatives and proper container