Preformulation by Dhiraj Shrestha
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This document discusses preformulation testing, which involves investigating the physical and chemical properties of a new drug substance alone and when combined with excipients. The overall objective is to generate information to help formulate stable and bioavailable dosage forms. Key aspects covered include organoleptic properties, purity, particle size and surface area. Common methods for analyzing these parameters, such as chromatography, microscopy, and gas adsorption, are also summarized. The goals are to provide critical data for developing optimized dosage forms that can be mass produced.
Preformulation by Dhiraj Shrestha
- 2. • Introduction : • Organoleptic Properties : • Purity : • Particle size, shape and surface area:
- 3. INTRODUCTION • Preformulation testing is the first step in rational development of dosage forms of a new drug substance. • It can be defined as an investigation of physical and chemical properties of a drug substances alone and when combined with excipients.
- 5. Objective: • The overall objective of preformulation testing is to generate information useful to the formulator in developing stable and bio- available dosage forms that can be mass produced . • Obviously , the type of information needed will depend on the dosage form to be developed.
- 6. PERFORMANCE OF PREFORMULATION STUDIES: • The formal preformulation studies should start at the point after biological screening, when a decision is made for further development of compound in the clinical trials. • Before the formal program , the preformulation scientist must consider the following : • 1.:Available physicochemical data ( including chemical structure , different salts available). • 2: Anticipated Dose.
- 7. • SELECTIVITY is very critical to success of preformulation program . Not all the preformulation parameter are determined for every new compound . Data , as they generated , must be reviewed to decide what additional studies must be undertaken. For Eg , • A detailed investigation of dissolution is not necessary for Very soluble compound . • On the other hand , particle size , surface area,
- 8. ORGANOLEPTIC PROPERTIES •A typical preformulation program should begin with the description of drug substance . •The color , odor, 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. •During manufacturing of different batches of new drug, the colour of early batches must be recorded by using descriptive terminology. A record of the colour of early batches will be useful for preparing the appropriate specification
- 9. Suggested terminology for organoleptic properties of pharmaceutical powders are COLOR ODOUR TASTE Off white Pungent Acidic Cream yellow Sulfurous Bitter Tan Fruity Bland Shiny Aromatic odorless Intense Sweet Tasteless
- 10. • The odour and taste may be suppressed by using appropriate flavors and excipients or by coating the final product. • The flavors , dyes and other excipients selected to overcome problems variable color and unpleasant odor and taste must be screened for their influence on the stability and bioavailability of active drug. • Many drug substances are irritating to skin . Such information may already be available or developed during the course of preformulation studies.
- 11. PURITY studies are must often performed in an analytical research and development group. But preformulation scientists must have some perception or some early knowledge of purity of drug substance . Early knowledge is necessary so that preformulation and clinical trial performance can not be compromise and it can improve the validity .It
- 12. • Occasionally an impurity can affect stability . • Eg.Metal contamination will affect certain classes of compound • Presence of impurity makes a compound toxic. • Eg: Presence of aromatic amines suspected to be carcinogenic. • For this some discussion must be initiated with the chemist preparing the material. so
- 13. • TLC. • HPLC. • Paper chromatography. • Gas chromatography Excellent tools for finding out the chemical homogeneity along with estimation of purity is given below---
- 14. TLC CHAMBER
- 15. HPLC
- 16. GC
- 17. PAPER CHR.
- 18. •It measures Impurity index(II) and homogeneity index (HI) specially from HPLC chromatography. All responses due to other component •Impurity index(II):---------------------------------------- --- Total response The responses are obtained as area measurement in the chromatographic procedure.
- 19. • The USP has proposed a related procedure called ordinary impurities test that estimates using TLC. The USP is proposing a general limit of 2% impurity for qualitative estimation of purity has been done by Gravimetric thermal analyses. • For quantitative estimation of purity has been done by Differential scanning calorimetry or by phase-rule solubility analysis. • ICH guidelines for impurity is given below
- 21. PARTICLE SIZE, SHAPE AND SURFACE AREA • Various chemical and physical properties of drug substances are affected by their particle size distribution and shape. The effect is not only on the physical properties of the solid drugs but also on their biopharmaceutical behavior E.g. bioavailability of griseofulvin and Phenacetin is directly related to the particle size. distribution .Poorly soluble drugs shows greater bioavailability in the finely subdivided state then as a coarse-material • Size also plays a role in the homogeneity of the final tablet. When large difference in the size exist between the active components and excipients. So to control non homogeneity of diluents and API sieving can be done. Not only size but shape also influence the flow and mixing efficiency of powders and granules. • Size can also play a factor in stability, fine particles are relatively more prone to attack by oxygen, heat, light, humidity and interacting excipients than coarse materials.
- 22. • Eg:Weng and Parrol investigated influence of particle size of Sulfacetamide on its reaction with Phthalic anhydrous in 1:2 molar compacts after 3 hr at 95OC ,which clearly says that the reactivity occurs due to decreasing of particle size of Sulfacetamide. So particle size should be maintain and control it. • The particle size of a new drugs having size above 100µm in diameter is probably safe to grind . If material consists of particle size 30µm or less than that are unnecessary for grinding. • Grinding should reduce coarse materials to ,preferably the 10 to 40 µm ranges. The particle size has an effect on dissolution rate and solubility . It is shown Noyes-whitney equation--- dc/dt =KS (Cs-Ct)
- 23. METHODES FOR DETERMINING PARTICLE SIZE • Many method are available for particle size determining few method is given below---- • 1. Optical microscopy : According to this method, an emulsion or suspension diluted or undiluted, is mounted on a slide or ruled cell and placed on a mechanical stage, where with the help of micrometer the size of the particle may be estimated. The photograph can be taken from which a slide is prepared and projected onto screen for measurement . • Disadvantage:
- 25. 2.Sieving This method utilizes a series of standard sieves calibrated by the National Bureau of standard. Sieve produced by photoetching and electroforming techniques now available with apertures from 90 µm down to as low 5 µm
- 26. Approximate sieve number* Approximate % sieving area Nominal mesh aperture size mm Tolerance average aperture size + mm 4 55 4.0 0.136 8 48 2.0 0.07 10 46 1.7 0.06 12 44 1.4 0.05 16 41 1.0 0.03 um + um 22 37 710 25 25 36 60 21 30 38 500 18 36 36 425 15 44 38 355 13 60 37 250 13 (9.9)** 85 35 180 11 (7.6) 100 36 150 9.4 (6.6) 120 34 125 8.1 (5.8) 150 36 106 7.4 (5.2) 170 35 90 6.6 (4.6) 200 36 75 6.1 (4.1) 240 34 63 5.3 (3.7) 300 35 53 4.8 (3.4)
- 27. •3.sedimentatin rate : Sedimentation rate ,in which particle size is measured by the terminal settling velocity of particles through a liquid medium in a gravitational or centrifugal environment (range 0.8-300µm) Sedimentation rate may be calculated from stokes’ law dx/dt = d²(ρ₁ - ρe)g/18η Here d – diameter of particle ρ₁ , ρe - density of particle , medium G – gravitational constant η – viscosity of medium •4.light scattering (0.2-500µm).
- 29. METHODES FOR DETERMINING SURFACE AREA The surface area of a powder can be determined from the knowledge of particle size distribution . Two methods are available that permits direct calculation of the surface area. • Amount of a gas or liquid solute that is adsorbed on the sample of powder to form monolayer.
- 30. • Adsorption method: • Particle with a large specific surface are good adsorbents for the gases and of solutes from solution .In determining the surface of the adsorbent ,the volume in cubic centimeters of gas adsorbed per gm of adsorbent may plotted against the pressure of the gas at constant temperature to give type II isotherm (line in a map). • The adsorbed layer is monomolecular at low pressures and becomes multimolecular at
- 31. • Air permeability method: The principle resistance to flow of a fluid, such as air, through a plug of compacted powder is the surface area of the powder. The greater the surface area per gram of powder, the greater the resistance to flow. Hence permeability, for a given pressure drop across the plug, is inversely proportional to specific surface.
- 32. • References: • Pharmaceutical dosage forms :Tablets Volume1 ----By,Leon Lachman. • Pharmaceutical dosage forms and drug delivery systems --- By Howard C.Ansel. • Aultons Pharmaceutics—Third edition ---By Michael E.Aulton. • Physical pharmacy ---By Alfred Martin • Indian Pharmacopoeia 1997. • ICH Guidelines.