PREFORMULATION.pptx

B.PHARM V SEMESTER

1. PHYSICO C HEM I C AL PARAMETERS OF PREFORMULATION STUDIES BY : BALASUNDARESAN M 1

2. INTRO D UC T ION WH A T IS P RE F OR M UL A TI O N? “It is the study of the physical and chemical properties of the drug prior to compounding process”. Preformulation commences when a newly synthesized drug shows sufficient pharmacologic promise in animal models to warrant evaluation in man. These studies should focus on physicochemical properties of new compound that affect drug performance & development of efficacious dosage form. This properties may provide; A rationale for formulation design Support the need for molecular modification 2

3. Goals of preformulation To establish the physicochemical parameters of a new drug. To establish its physical characteristics . To establish its compatibility with common excipients. Providing a scientific data to support the dosage form design and evaluation of the product efficacy and stability. In short Quantization of physical and chemical properties will assist in developing a; Stable Safe Effective formulation 3

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5. THE MA J OR AR E A S OF P R E F O RMU L A TION STUDY I. Physical description and Bulk Characterization: Crystallinity and Polymorphism Hygroscopicity Fine Particle Characterization Thermal Effects Powder Flow Properties 5

6. II . S o lubili ty A n a l y s i s : Ionization Constant- pKa pH Solubility Profile Common Ion Effect Solubilization Partition Coefficient Dissolution III . St a b ili ty A n a l ys i s : S o li d - St a t e St a b ility Solution-Phase Stability Compatibility Studies: Stability in the Presence of Excipients 6

7. PHYSICAL CHARACTERIZATION Drugs can be used therapeutically as solids, liquids and gases. Liquid drugs are used to a much lesser extent than solid drugs and even less frequently than gases. Solid materials are preferred in formulation work because of their ease of preparation into tablets and capsules. The majority of drug substances in use occur as solid materials. Most of them are pure chemical compounds of either: Amorphous or Crystalline in nature 7

8. P HYS I C A L D E SCR I P T I ON A N D B U L K CHARACTERIZATION 8 Bulk properties for the solid form such as particle size, bulk density and surface morphology are likely to change during process of development. The various physical and bulk characteristics are explained as follows:

9. C R YS T A LLI N I T Y AND PO L YMORPHISM Solid drug materials may occur as: Amorphous (higher solubility) Crystalline (higher stability) The amorphous or crystalline characters of drugs are of great importance to its ease of formulation and handling, its chemical stability and its biological activity. 9

10. AMORPHOUS DRUGS A m o r p h o u s d r u g s h a v e r a n do m l y arra n g e d a to m s or molecules. A m o r p h o u s f o r m s are t y pi c a l l y p re p ar e d b y ; precipitation, lyophilization, or rapid cooling method. Advantage: Amorphous forms have higher solubilities as well as dissolution rates as compared to crystalline forms. Disadvantage: U p o n s t o r a g e, s o m e t i m es a m o r p ho u s s o l i d s t e n d to revert to more stable forms. This instability can occur during bulk processing or within dosage forms. 10

11. E.g. Novobiocin : It is inactive when administered in crystalline form, but when they are administered in the amorphous form, absorption from the gastrointestinal tract proceeds rapidly with good therapeutic response. 11

12. CRYSTALLINE DRUGS 12 Crystals are characterized by repetitious spacing of constituent atoms or molecules in a three dimensional array. Crystalline forms of drugs may be used because of greater stability than the corresponding amorphous form. For example: the crystalline forms of penicillin G as potassium or sodium salt is considerably more stable and result in excellent therapeutic response than amorphous forms.

13. POLYMORPHISM 13 Polymorphism is the ability of the compound to crystallize as more than one distinct crystalline species with different internal structure. Formation of different polymorphs depends on solvents, temperature, pressure, rate of cooling, etc . Polymorphic transitions can also occur during milling, granulating, drying and compressing operations Different polymorphs vary in physical properties such as dissolution, solid‐state stability, compatibility, etc

14. Significance of polymorphism: 14 D i f fer e n t po l y m o r p h s e x hib i t s di f f er e n t s o lu b ili t i e s , therapeutic activity and stability. Che m i c a l s t a b i li ty a n d s o l ub i li ty c h a ng es d u e to polymorphism can have an impact on drug’s activity.

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16. THER M A L ANA L Y S I S Differential scanning calorimetry and Differential thermal analysis: [DSC & DTA] Measure the heat loss or gain resulting from physical or chemical changes within a sample as function of temperature. Thermo gravimetric analysis (TGA): It measure changes in sample weight as a function of time (isothermal) or function of time (isothermal) or temperature. Desolvation and decomposition processes are fr e qu e n t l y m on it o red b y TG A . 17

17. Applications: 18 Purity, polymorphism, solvation, degradation, and excipient compatibility. Thermal analysis can be used to investigate and predict any physicochemical interactions between components in the formulation. It is used for selection of chemically compatible excipients.

18. X - R A Y D IFF RAC TION 19 It is an important technique for establishing the batch- to batch reproducibility of a crystalline form. Each diffraction pattern is characteristic of a specific crystalline lattice for a given compound. Applications: Q u a nti t a t i v e ra t io s o f t w o po l y m o r p h s a n d th e i r percentages of crystallinity may be determined. crystalline f o r m s can be Mixtures of different a n a l y zed u si n g no r m a li z e d intensities at specific angles, which are unique for each crystalline form.

19. H Y G R O SC O PICIT Y 20 Many drugs , particularly water-soluble salts, have a tendency to adsorb atmospheric moisture. Changes in moisture level can greatly influence many parameters such as ; chemical stability, flowability, and compatibility. Adsorption and equilibrium of moisture content can depend upon ; atmospheric humidity, temperature, surface area, exposure, and the mechanism for moisture uptake.

20. Hygroscopic substances : It adsorbs water because of hydrate formation or specific site adsorption. Deliquescent materials: A d s o rb s u f f i c i e n t w a t er t o d i ss o l v e c o m p l e t e l y , as observed with sodium chloride on a humid day. A n a l y t i c m e th od s f o r m on i t o r i n g t h e m o i s t u re l e v e l are g ra v i m e t r i c ( w e i gh t g a i n e d ), K a rl F is cher titration, or gas chromatography) according to the desired precision & the amount of moisture adsorbed onto the drug sample. 21

21. FINE PARTICLE CHARACTERIZATION Certain physical and chemical properties of drug substances are affected by the particle size Size, shape & surface morphology of drug particles affect the flow property, dissolution &chemical reactivity of drugs. Significance of Particle Size : distribution including; drug dissolution rate, content uniformity, texture, stability, flow characteristics, and 22 sedimentation rates.

22. Par t i c l e s i z e 23 s ig n i f i c a nt l y in f lu e n c e s t h e o r a l absorption profiles of certain drugs. Sa t is f a c t o ry c o n t e n t u n i f o r m it y i n s oli d d o s a g e forms depends to a large degree on particle size and the equal distribution of the active ingredient throughout the formulation.

23. METHODS TO EVALUATE PARTICLE SIZE AND DISTRIBUTION 24 Sieving or screening Optical microscopy Sedimentation Stream scanning. Sieving or screening: D is a d v a n t a g e : I t r e q ui r es a r e l a t i v e ly l a r g e s a m pl e size. A dv a n t a g e : S i m pl i c i t y i n t e c hn i qu e a n d e qu ip m e n t requirements.

24. Optical microscopy: It is the first step in the determination of particle size and shape for new drug substance. Disadvantage: Quantitative evaluations need minimum 1000 particles (tedious and time consuming). The slide must be representative of the bulk of the material . Sedimentation: It u t i li ze t h e r e l a ti o n s h i p b e t w e e n r a t e o f f a l l of particles and their size 25

25. Stream scanning: Technique utilizes a fluid suspension of particles which pass the sensing zone where individual particles are sized, counted & tabulated. Sensing units are based on ; light scattering transmission, as well as conductance. The popular unit in the pharmaceutical industry for this purpose is the Coulter Counter Advantages: The unit electronically size, count and tabulate the individual particles that pass through the sensing zone and data is obtained in a short time with reasonable accuracy. 26

26. Thousands of particles can be counted in seconds and used to determine the size distribution curve. It is a powerful tool and can be used for evaluation of parameters as crystal growth in suspension formulation. 27

27. SURFACE MORPHOLOGY 28 It is observed by Scanning Electron Microscopy (SEM), which serves to confirm the physical observations related to surface area. Surface morphology of drug can provide greater area for various surface reactions such as; degradation, dissolution, or hygroscopicity. Surface roughness leads to poor powder flow characteristics of powders due to friction and cohesiveness

28. BULK DENSITY 29 Bulk density of a compound varies with the method of crystallization, milling, or formulation. Importance of bulk density: Knowledge of the true and bulk densities of the drug substance is useful in forming idea about the size of the final dosage form. The density of solids also affects their flow properties .

29. POWDER FLOW PROPERTIES 30 Flow properties are significantly affected by: Changes in particle size, density, shape, and adsorbed moisture, which may arise from processing or formulation. The powder flow properties can be characterized by the following methods:

30. The Angle O f Repo se : 31 It is the maximum angle between the surface of a pile of powder and horizontal plane Tan θ= h/r T h e r o ug h er a n d m o re i rr e g u l ar t h e s u r face o f t h e particles, the higher will be the angle of repose. Lower values indicates better flow characteristics.

31. Angle of repose Type of flow < 20 Excellent flow 20-30 Good flow 30-34 Passable >40 Poor flow 32 The acceptance criteria for angle of repose are:

32. Compressibility: It can be characterized by the following methods; Carr’s compressibility index Hausner`s ratio 1. Carr’s compressibility index: Car r ’ s i n d ex ( % ) = T a p p ed d e n sit y – b u l k d e n sit y x100 Tapped density By decreasing the bulk and tapped density good flow properties can be obtained. 33

33. Carr’s index Type of flow 5-15 Excellent 12-16 Good 18-21 Fair to passable 23-35 Poor 33-38 Very poor >40 Extre m ely poo r 34 The acceptance criteria for carr`s index are :

34. 2. Hausner `s ratio : H a u s n e r `s ra t io = Tap p e d densit y X 100 bulk density The acceptance criteria for Hausner`s ratio are : : Hausner`s ratio Type of flow < 1.25 Good flow > 1.5 Poor flow 1.25-1.5 Glidant addition required >1.5 Glidant doesn’t improve flow 35

35. S O LUB I L I TY T h e s ol u bi l i ty o f d r u g i s a n i m po r t a n t physicochemical property because it affects the rate of drug release consequently, in t o t h e d i sso l ut i o n m e d ium a n d th e th e r a p e u t i c e f f i c acy o f the pharmaceutical product. The solubility of a material is usually determined by the equilibrium solubility method, which employs a saturated solution of the material, obtained by stirring an excess of material in the solvent for a prolonged period until equilibrium is achieved. General rules – 1. Polar solutes dissolve in polar solvents 2. Non-polar solutes dissolve in non-polar solvents 36

36. Common solvents used for solubility determination are: Water Polyethylene Glycols Propylene Glycol Glycerine Sorbitol Eth y l A l cohol Methanol Benz y l A l cohol Isopropyl Alcohol Tweens Polysorbates Castor Oil Peanut Oil Sesame Oil Buffers at various pHs 37

37. S OLUBILITY DETERMINATION Description Approximate weight of solvent(g) necessary to dissolve 1g of solute Solubility(%w/v) Very soluble <1 10-50 Freely soluble 1-10 3.3-10 Soluble 10-30 1-3.3 Sparingly soluble 30-100 0.1-1 Slightly soluble 100-1000 0.01-.1 Very slightly soluble 1000-10000 0. 1 - 0.1 38 Poorly soluble >10000 <0.01

38. For a compound containing basic or acidic functional groups, solubility at a given pH is influenced by the compound’s ionization characteristics. The solubility of a compound in aqueous media is greater in the ionized state than in the neutral state. Thus, solubility of ionizable compounds is dependent on the pH of the solution. The method for the determination of pKa according to the nature of drug can be explained as: 39 Ionization constant (pKa)

39. Nature of drug Ionization pKa Very weak acid Unionized at all pH >8 Moderately weak acid Unionized at gastric pH-1.2 2.5-7.3 Strong acid Ionize at all pH <2.5 Very weak base Unionize at all pH <5 Moderately weak base Unionize at intestinal pH 5-11 Strong base Ionize at all pH 40 >11 pKa Determination By Nature of Drug

40. Determination of the dissociation constant for a drug capable of ionization within a pH range of 1 to 10 is important since solubility, and consequently absorption, can be altered by changing pH. The Henderson-Hasselbalch equation provides an estimate of the ionized and un-ionized drug concentration at a particular pH. For acidic compounds : pH = pKa + log ([ionized drug]/[ un-ionized drug]) For basic compounds : pH = pKa + log ([un-ionized drug]/[ionized drug]) 41

41. Methods for determination of pKa: The various methods for the determination of pKa are; Potentiometric method Spectrophotometric method Solubility method Conductometric method 42

42. Partition coefficient Partition coefficient (oil/water) is a measure of a drug's lipophilicity and an indication of its ability to cross cell membranes. Define: It is defined as the ratio of un-ionized drug distributed between the organic and aqueous phases at equilibrium. P o/w = (C oil /C water ) equilibrium Drugs having values of P much greater than 1 are classified as lipophilic, whereas those with partition coe f fic i en t s m u ch l e s s t h a n 1 are in d i c at i v e o f a hydrophilic drug 43

43. Stability studies Preformulation stability studies are usually the first quantitative assessment of chemical stability of a new drug. These studies include both solution and solid state experiments under conditions typical for the handling, formulation, storage, and administration of a drug candidate as well as stability in presence of other excipients. 44 Fac t o r s a f f e c ti n g c h e m i c a l s t a b i li t y rational dosage form design include ; Temperature, pH Dosage form diluents

44. The effect of pH on drug stability is important in the development of both oral and parenteral dosage forms e.g. acid labile drugs intended for oral administration must be protected from the highly acidic environment of the stomach. Buffer selection for parenteral dosage forms will also be largely based on the stability characteristics of the drug. 45

45. R EF E RE N CE S : 46 Handbook of preformulation by Srafaraz K. niazi Dosage form design by Dr. Javed ali, Dr. khar ,Dr.Ahuja,1 st edition ,2004-2005 H. Brittain, Polymorphism in Pharmaceutical Solids, Marcel Dekker, Inc., 1999.

46. Thank you 47