Download Pre-formulation Technology and more Slides Pharmacy in PDF only on Docsity!
Preformulation Technology
DEVELOPMENT PHASES
The development of new active entities (NAEs) undergoes a lengthy and expensive cycle that varies greatly depending on the type of drug developed. What follows is a typical development cycle: Stage 1: Lead Finding or Establishing Directions (One to Two Years) Stage 2: Candidate Drug Screening (One to Ten Years) Stage 3: Candidate Drug Selection (One to Two Years) Stage 4: Preclinical Studies (One to Two Years) Stage 5: Phase I Clinical Studies (One to Two Years) Stage 6: Phase II and Phase III Studies and Launch (Four to Six Years) Stage 7: Postmarket Surveillance (Three to Five Years) Phase IV Studies
Investigational new Drug Application (IND)
New Drug Development Process
New Active Entity (NAEs) Sources:
- Organic Synthesis
- Molecular Modification
- Isolation from Plants Preclinical Studies Including:
- Chemistry
- Physical Properties
- Biological o Pharmacology o ADME o Toxicology
- Preformulation Preclinical Studies (Continued) Plus:
- Long-term Animal Toxicity
- Product Formulation
- Manufacturing and Controls
- Package and Label Design Clinical Trials
- Phase I
- Phase II
- Phase III
Preformulation testing is the first step in the rational development of dosage forms of a drug substance. It can be defined as an investigation of physical and chemical properties of a drug substance alone and when combined with excipients. A detailed understanding of the properties of the drug substance is essential to minimize formulation problems in later stages of drug development, reduce drug development costs, and decrease the product’s time to market (i.e., from drug substance to drug product).
The goals of preformulation studies are to:
➢ choose the correct form of the drug substance
➢ evaluate its physical properties, and
➢ generate a thorough understanding of the material’s
stability under the conditions that will lead to
development of an optimal drug delivery system.
Following tests are carried out under preformulation: INITIAL PHYSICOCHEMICAL CHARACTERIZATION p K a Determinations Many potential candidate drugs are weak organic acids (for example, frusemide, phenobarbitone, benzoic acid) or bases (for example, neomycin, diphenhydramine, lignocaine) or their salts.
concentrations
2 >0.99 soluble
Effects of pH and pKa on the solubility in water of a weakly basic
drug
pH-pKa Approximate mole fraction of ionized drug Solubility in water <- 2 >0.99 Soluble
- 1 0.91 Soluble except at very high concentrations 0 0.50 Soluble at low concentrations 1 0.09 Insoluble
2 <0.01 Insoluble
pKa values can be determined by various instrumental methods, such as spectrophotometry, conductometry, potentiometry etc. pKa values help to: (i) calculate the change of solubility with pH (ii) manipulate the pH to increase solubility and formulate solutions (iii) select suitable salt form of the drug if needed. Organoleptic Properties A typical preformulation program should begin with the description of the drug substance. The color, odor, and taste of the new drug must be recorded using descriptive terminology. It is important to establish a standard terminology to describe these properties in order to avoid confusion among scientists using different terms to describe the same property. Suggested Terminology to Describe Organoleptic Properties of Pharmaceutical Powders: Color Odor Taste Off-white Pungent Acidic Cream yellow Sulfurous Bitter Tan Fruity Bland
❖ Paper chromatography ❖ Gas chromatography ❖ differential and gravimetric thermal analyses ❖ Differential scanning calorimetry (DSC) ❖ Phase-rule solubility analysis ❖ Melting point ❖ Hot-stage microscope ❖ X-ray powder diffraction Figure: HPLC chromatograph of a typical batch of an experimental drug.
Particle Size, Shape and Surface Area Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes. The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior. For example, the bioavailability of griseofulvin and phenacetin is directly related to the particle size distributions of these drugs. Solid-dispersion Finely subdivided state ▪ De-mixing ▪ Electrostatic effects ▪ Undue stickiness ▪ Lack of flowability ▪ Flow and mixing efficiency of granules ▪ Atmospheric attack ▪ Grinding (only to 100μm particles) Table: Common Techniques for Measuring Fine Particles of Various Sizes Particle size Technique (μm) Microscopic 1 - 100 Sieve > Sedimentation >
A = absorbance (given by the UV spectrophotometer); b= path length; c= concentration of the drug in solution; a = proportionality constant known as absorption coefficient, Solubility Aqueous solubility Determination of aqueous solubility is important for two reasons: (i) Whether solution dosage form can be easily prepared for oral and parenteral administration. (ii) Whether bioavailability problems will occur due to low solubility. Kaplan’s suggestion: Aqueous solubility over the pH range 1-7 at 37°C Below 0.1% (< 1 mg/ml) ↓ Potential bioavailability problem is
(1 mg/ml – 10 mg/ml) ↓ Bioavailability problem may occur Above 1 % (> 10 mg/ml) ↓ Bioavailability problem is
likely to occur not expected A drug must be in solution (that is molecularly dispersed) before it can pass any biological membrane. Thus, absorption, distribution, excretion, action etc. of a drug will only take place when it is dissolved (molecularly dispersed) in the relevant biological fluid. Intrinsic solubility (C 0 ): When the purity of a drug sample can be assured, the solubility of a weak acidic drug in an acidic medium or solubility of a weak basic drug in an alkali medium is termed as Intrinsic solubility (C 0 ). This is the fundamental solubility of the drug species when it remains completely (100%) unionized. Intrinsic solubility should be determined at two different temperatures - (i) 4°C to assess physical stability. (ii) 37°C for biopharmaceutical evaluation. Solubility in other solvents Determination of solubility of a drug in other solvents and mixture of solvents is also needed. The information is needed-
Salt formation If a weak acidic or weak basic drug has insufficient solubility, its solubility can be improved by suitable salt formation. Salts are always more soluble than the corresponding acid or base under all pH conditions. Some of the common counter-ions used for salt formation are- For acidic drugs For basic drugs Potassium Sodium Calcium Zinc Hydrochloride Sulfate Phosphate Maleate Tartrate Lactate Citrate Acetate Examples of some drugs used in the salt form- Parent drug Salt form which are used Promethazine Salbutamol Diclofenac Chlorpheniramine Atropine Promethazine hydrochloride Salbutamol sulfate Diclofenac sodium Chlorpheniramine maleate Atropine sulfate
Besides increasing solubility, other factors are also taken in consideration while choosing a salt form, such as - (i) chemical stability (ii) physical properties (iii) hygroscopicity (iv) biocompatibility (v) bioavailability (vi) intensity of response etc. Changing a drug to its salt form is likely to affect all of the parameters mentioned above although the inherent pharmacology of the molecule is usually not changed. Dissolution Dissolution is the process by which a solid get dissolved and goes into solution. Rate of dissolution is related to the time needed to get dissolved, Extent of dissolution is related to the amount of solid which get dissolved. Absorption and bioavailability are affected by both rate and extent of drug dissolution.
Partition coefficient Partition coefficient indicates how a solute will distribute itself between two immiscible liquids. It gives the idea about the relative hydrophilicity and lipophilicity of a compound. If a solute is added in two immiscible liquids than it will distribute itself between the two phases in such a way so that the ratio of the concentrations of the solute in the two layers is a constant at constant temperature. This constant is known as distribution coefficient or partition coefficient. Partition coefficient K or P = C 1 / C 2 Solvent 1 C 1 C 2 Solvent 2
In Pharmacy, the concentration of the organic phase is written in the numerator and the concentration of the aqueous phase is written in the denominator. Thus, K or P = Co/Cw (concentration in the organic phase concentration in the aqueous phase) Partition coefficient is also expressed as log P Larger is the value of partition coefficient of a drug, greater is its lipophilicity. Knowledge of partition coefficient of a drug gives the following information - (i) how quickly or slowly absorption and bio-membrane transportation will occur. Biological membranes are lipid (organic) in nature whereas blood and other body fluids are aqueous in nature. Therefore, drugs having high partition coefficient values will have greater affinity for biological membranes and transport through the membranes will be favored. Bio-membrane transportation will be slower for drugs having smaller P values, Blood Bio-membrane DRUG (^) DRUG DRUG DRUG Small P value Large P value
