PREFORMULATIONS Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D Department of Pharmaceutics Faculty of Pharmacy Omer Al-Mukhtar University Tobruk, Libya /06/101 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

CONTENTS Concept of preformulation Physical properties (description, particle size) Partition coefficient Polymorphism, Solubility Salt formation Chemical properties Drug stability Hydrolytic degradation Drug-excipient interaction Permeability Proteins and peptides Formulation ingredients References 2014/06/102 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Concept of Preformulation Prior to the development of tablets, capsules and injections are major dosage forms, it is essential that certain fundamental physical and chemical properties of the drug molecule and other derived properties of the drug powder are determined. This information dictates many of the subsequent events and approaches in formulation development. This first learning phase is known as preformulation. 2014/06/103 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Importance of Preformulation  To form desired quality dosage forms.  To achieve high degree of uniformity, physiological availability and therapeutic qualities.  To develop an optimum dosage form.  For targeted drug delivery systems.  For patient compliance.  To minimize cost of finished product.  To minimize errors in formulation of dosage form. 2014/06/104 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Physical properties (Description) The physical properties of drug molecules can affect the structure and stability of formulations and may also alter the bioavailability of the drugs from the dosage forms. Hence, physical properties of drugs are important in the dosage form design. The following physical properties influence dosage form design. 1.Particle size 2.Polymorphism 3.Salt 2014/06/105 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Physical properties (Particle size) Small particles are particularly important in low-dose high-potency drug candidates, as large particle populations are necessary to ensure adequate blend homogeneity, and for any drug whose aqueous solubility is poor, as dissolution rate is directly proportional to surface area. Commercial powders consist of aggregation of small particles. The particles size is usually denoted as coarse powder, fine powder and very fine powder etc. 2014/06/106 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

In aerosols the particle size of 0.5 to 4 microns is optimal to exhibit its action. Particle size is also an important parameter in determining sedimentation rates in suspensions and emulsions. The simplest method for small quantities is the microscope. The Coulter Counter and laser light scattering are widely used for routine bulk analysis and research. Physical properties (Particle size) 2014/06/107 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Partition coefficient When a solute is shaken with two immiscible liquids, solute itself distribute in the liquids in such a way that the concentration solute in the both the liquids will be the constant temperature. If C 1 and C 2 are the concentration of the substances in solvent 1 and 2, the distribution coefficient or partition coefficient K = C 1 /C 2. Partition coefficients of a drug are helpful in the study of its absorption, distribution, metabolism and elimination. 2014/06/108 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Polymorphism It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice. Different crystalline forms are called polymorphs. Polymorphs are of 2 types 1. Enatiotropic 2. Monotropic 2014/06/109 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Parameters of polymorphs to investigated are 1.No.of polymers that exist 2. Relative degree of stability 3. Presence of glassy state 4. Stabilization of metastable forms 5. Solubility 6. Temperature stability range 2014/06/1010 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Solubility The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution.  If solubility is <1mg/ml indicates need for salt formation to improve solubility.  If solubility is <1mg/ml in pH= 1 to 7, preformulation study should be initiated.  Solubility should ideally be measured at two temperatures: 4°C and 37°C.  4°C to ensure Physical stability.  37°C to support Biopharmaceutical evaluation. 2014/06/1011 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Descriptive Solubility 2014/06/10 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 12 DescriptionParts of solvent required for one part of solute Very soluble < 1 Freely soluble Soluble Sparingly soluble Slightly soluble Very slightly soluble ,000 Insoluble > 10,000

Solubility Analysis  Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate.  For e.g. A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH.  Analytic method that are particularly useful for solubility measurement include HPLC, UV spectroscopy, Fluorescence spectroscopy and Gas chromatography.  Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug. 2014/06/10 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 13

Salt formation Salts prepared from strong acids or bases are freely soluble but very hygroscopic. It is often better to use a weaker acid or base to form the salt, provided any solubility requirements are met. A less soluble salt will generally be less hygroscopic and form less acidic or basic solutions. The dissolution rate of a particular salt is usually much greater than that of the parent drug. Sodium and potassium salts of weak acids dissolve much rapidly than do the parent acids. 2014/06/1014 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Chemical properties Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone. The interior cavity is hydrophobic and the outside of the molecule is hydrophilic. 2014/06/1015 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Drug stability The potency should not fall below 95% under the recommended storage conditions and the product should still look and perform as it did when first manufactured. Drug degradation occurs by four main processes; 1.Hydrolysis 2.Oxidation 3.Photolysis 4.Trace metal catalysis 2014/06/1016 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Hydrolytic degradation The most likely cause of drug instability is hydrolysis. Water plays a dominant role and in many cases it is implicated passively as a solvent vector between two reacting species in solution. The solution is often saturated, so that studies in dilute solution can be completely misleading. Hydrolytic reactions involve nucleophilic attack of labile bonds When this attack is by a solvent other than water it is known as solvolysis 2014/06/1017 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Some interactions between the drug molecules and the additives are given below, 1.Carboxymethyl cellulose forms complex with quinine, procaine etc. 2.Carrageenan forms complex with chlorpromazine, antihistamine etc. 3.Sodium alginate forms complex with Ca ++ ions. 4.PVP and polyethyleneglycol interact with phenolic groups of resorcinol, tannic acid leading to precipitation. Drug-excipient interaction 2014/06/1018 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Permeability Measuring the rate of permeation across membranes that are used to gain an assessment of oral absorption in humans. These range from computational predictions and both physicochemical and biological methods. The biological methods can be further subdivided into in vitro, in situ and in vivo methods. In general, the more complex the technique the more accurate is the assessment of oral absorption in humans. 2014/06/1019 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Proteins and peptides Nowadays most proteins and peptides used in therapy or under development are produced by recombinant DNA or hybridoma technology (known as biotechnology or biotech products). It is clear that pharmaceutical proteins and peptides offer special challenges to the pharmaceutical formulator. Proteins and peptides structure, being stabilized by relatively weak physical bonds, is readily and irreversibly changed. Examples are human insulin, erythropoietin, monoclonal antibodies, cytokines and interferons 2014/06/1020 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

Formulation ingredients ComponentsQuantity Phenobarbital65.0 mg Lactose (fine powder)40.0 mg Starch 10.0 mg Starch pasteq. s. Talc10.0 mg Mineral oils4.0 mg 2014/06/1021 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

THANK YOU /06/1022 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.