PREFORMULATION STUDIES.pptx

PREFORMULATION STUDIES

1. PREFORMULATION STUDIES Reshma Fathima K Assistant Professor Grace College of Pharmacy, Palakkad

2. S.No Parameters Evaluation parameters 1. Stability Solid State Solution   Temperature, Light, humidity, Solvent,pH 2. Solid State Compatibility TLC  FTIR 3. Physico-chemical Properties Color, odor, particle size, shape crystallinity Molecular Structure and Weight, melting point 4. Thermal Analysis Profile Solubility Water and other solvent, pH DTA, DSC,TGA Salt forms, co-solvent, Complexation , pro-drug 5. Absorbance Spectra UV, IR 6. Other properties Hygroscopicity Potential Bulk characterization Volatility, optical activity, solvate formation Crystallinity and polymorphism 7. Physico-mechanical Properties Bulk and Tapped density, compressibility Photomicrograph 8. In Vitro Availability Properties  Rat Everted Gut Technique Dissolution and analysis of Drug Crystal, pallets 9. Other Studies Plasma Protein-Binding, Ionization Constant Effect of Compatible Excipients on dissolution, Kinetic Studies of Solution Degradation, Use of Radio- labeled Drug Preformulation is defined as the phase of research and development in which preformulation studies characterize physical and chemical properties of a drug molecule in order to develop safe, effective and stable dosage form. Table 1 describes some evaluation parameters used in preformulation of drug development.

3. OBJECTIVES To generate useful data needed in developing stable and safe dosage forms that can be manufactured on a commercial scale. To provide a complete knowledge and understanding of charateristics of a drug molecule before development of a dosage forms. To improve bioavailability. GOALS To establish the physico -chemical parameters of a new drug entity To determine its kinetic rate profile of drug substances. To establish its compatibility of drug molecule with common excipients To choose the correct form of a drug substance.

4. PRINCIPLE AREAS OF PREFORMULATION ORGANOLEPTIC PROPERTIES Color Odour and taste BULK CHARACTERIZATION Crystallinity and polymorphism Hygroscopicity Fine particle characterization Powder flow SOLUBILITY ANALYSIS Ionization constant – pKa pH solubility Profile Common ion effect- Ksp Thermal effects Solubilization Partition coefficient Dissolution  

5. STABILITY ANALYSIS Stability in toxicology formulations Solution stability pH stability profile Solid state stability Bulk stability Compatibility Organoleptic properties: Color :  It should be Unappealing to the eye and determined by either instrumental methods or visible method that varies from batch to batch. Record of early batches and establishing “specs” is very useful for later production. Coating of body in variable color can be done if found undesirable. Odor and taste: For unpalatable drug use of less soluble chemical form or suppress it by flavors , excipients, coating etc. Drug substances which irritating to skin should be handle with precautions. Flavors , dyes, excipients used will affect stability and bioavailability. Color may be off-white, cream yellow, tan, shiny. Odor may be pungent, sulfurous , fruity, aromatic and odorless . Taste may be acidic, bitter, bland, intense, sweet and tasteless.

6. Bulk characterization studies It is needed to identify all the solid forms that may exist as a consequence of the synthetic stage such as the presence of polymorphs. Bulks properties such as particle size, bulk density, surface morphology may be changed during the development process and to avoid mislead predictions of solubility and stability which depends on a particular crystalline form. Bulk characterization testing includes Crystallinity Crystal habit & internal structure of drug can affect bulk & physicochemical property of molecule. Crystal habit is description of outer appearance of crystal. Internal structure is molecular arrangement within the solid. Change with internal structure usually alters crystal habit. Eg . Conversion of sodium salt to its free acid form produce both change in internal structure & crystal habit .

7. Different shapes of crystals Depending on internal structure compounds is classified as 1. Crystalline 2. Amorphous Crystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three dimensional array. In amorphous form atom or molecule are randomly placed. Solubility & dissolution rate are greater for amorphous form than crystalline, as amorphous form has higher thermodynamic energy. Eg . Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption.

8. 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  The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph. Eg . Sulphur . One polymorph which is unstable at all temp. & pressure is called as Monotropic polymorph. Eg . Glyceryl stearate.

9. Polymorphs differ from each other with respect to their physical property such as • Solubility • Melting point • Density • Hardness • Compression characteristic Eg . 1) Chloromphenicol exist inA,B & C forms, of these B form is more stable & most preferable.

10. ANALYTICAL METHODS FOR THE CHARACTERIZATION OF SOLID FORMS  Microscopy  Hot stage microscopy  Thermal analysis  X-ray diffraction  Infrared (IR) spectroscopy  Proton magnetic resonance (PMR)  Nuclear magnetic resonance (NMR )  Scanning electron microscopy (SEM)

11. Microscopy Material with more than one refractive index are anisotropic & appear bright with brilliant colors against black polarized background. The color intensity depends upon crystal thickness. Isotropic material have single refractive index and this substance do not transmit light with crossed polarizing filter and appears black. Advantage : By this method, we can study crystal morphology & difference between polymorphic form. Disadvantage : This require a well trained optical crystallographer, as there are many possible crystal habit & their appearance at different orientation.

12. Hot stage microscopy The polarizing microscope fitted with hot stage is useful for investigating polymorphism, melting point & transition temp. Disadvantage : In this technique, the molecules can degrade during the melting process.

13. Thermal analysis Differential scanning calorimetry (DSC) & Differential thermal analysis are (DTA) are particularly useful in the investigation of polymorphism. It measures the heat loss or gain resulting from physical or chemical changes within a sample as a function of temp. For characterizing crystal forms , the heat of fusion can be obtained from the area under DSC- curve for melting endotherms. Similarly, heat of transition from one polymorph to another may be calculated. A sharp symmetric melting endotherm can indicate relative purity of molecule. Abroad asymmetric curve indicates presence of impurities.

14. PARTICLE SIZE Particle size is characterized using these terms Very coarse, Coarse, Moderately coarse, Fine ,Very fine . Particle size can influence variety of important factors : - Dissolution rate - Suspendability - Uniform distribution - Penetrability - Lack of grittiness Methods to Determine Particle Size  Sieving (5µ-150µ)  Microscopy (0.2µ-100µ)  Sedimentation rate method (1µ-200µ)  Light energy diffraction (0.5µ-500µ)  Laser holography (1.4µ-100µ)

15. HYGROSCOPICITY  Many drug substances, particularly water –soluble salt forms, have a tendency to adsorb atmospheric moisture.  Adsorption and moisture content depend upon the atmospheric humidity, temperature, surface area, exposure and the mechanism of moisture uptake.  The degree of Hygroscopicity is classified into four classes:  Slightly hygroscopic: increase in weight is ≥ 0.2% w/w and < 2% w/w  Hygroscopic : increase in weight is ≥ 0.2 % w/w and < 15 % w/w  Very hygroscopic : increase in weight is ≥ 15% w/w  Deliquescent : sufficient water is adsorbed to form a solution Hygroscopicity is tested by: Samples are exposed to the moisture exposed to controlled relative humidity environments moisture uptake is monitored at different time points Analytical methods which is used are :  Gravimetry  Karl Fischer Titration  Gas chromatography

16. Fine particle characterization Certain physical and chemical properties of drug substances are affected by the particle size distribution, including drug dissolution rate, bioavailability, content uniformity, taste, texture color, and stability. In addition, properties such as flow characteristics and sedimentation rates, among others, are also important factors related to particle size. It is essential to establish as early as possible how the particle size of the drug substance may affect formulation and product efficacy. Methods of evaluation of particle size and distribution includes light microscope with a calibrated grid, Sedimentation techniques, Stream scanning, Coulter counter and Surface area determination by BET nitrogen adsorption method . Bulk density = Weight of sample/Bulk volume ( Vb ) Tapped density = Weight of sample/ Tapped volume ( Vt ) Powder flow properties The flow properties of powders are critical for an efficient tablet operation.During the pre-formulation evaluation of the drug substance, therefore, its flow ability characteristic should be studied, especially when the anticipated dose of the drug is large.Powders may be free flowing or cohesive (non free flowing).Flow properties are affected by changes in particle size, density, shape, electrostatic charges, and adsorbed moisture. It is characterized by Carr’s index and Hausner ratio, Angle of repose, rheology and thixotropy etc.

17. Angle of repose The static angle of repose “Ө” was measured according to the fixed funnel and free standing cone method. It is the maximum angle possible between the surface of a pile of powder and the horizontal plane. The funnel was clamped with its tip 2 cm above a paper placed on a flat horizontal surface. The tablet granules were poured through the funnel until the apex of the cone thus formed just reached the tip of the funnel. The mean diameters of the base of the powder cones were determined and the tangent of the angle of repose calculated using the equation, tan Ө = h/r h = height of granule pile r = radius of tablet granules Angle of repose (Ө) = tan 1 (h/r ). Hausner’s ratio This was calculated as the ratio of tapped density to the bulk density Hausner’s ratio= Tapped density/Bulk density Compressibility index (Carr’s Index ) Compressibility index was calculated using the equation Compressibility index = (Tapped density-Bulk density)/tapped density × 100