Preformulation studies(unit 1)

Preformulation Studies: Introduction to preformulation, goals and objectives, study of
physicochemical characteristics of drug substances.
a. Physical properties: Physical form (crystal & amorphous), particle size, shape, flow
properties, solubility profile (pKa, pH, partition coefficient), polymorphism.
b. Chemical Properties: Hydrolysis, oxidation, reduction, racemisation, polymerization
BCS classification of drugs & its significant
Application of preformulation considerations in the development of solid, liquid oral and
parenteral dosage forms and its impact on stability of dosage forms.

1. PREFORMULATION studies and bcs classification Prepared By: MOHAMMAD KHALID (Assistant Professor ) Krishna Pharmacy College, Bijnor (UP)

2. INTRODUCTION Preformulation studies are the investigations of physical and chemical properties of a drug substance, alone and in combination with other excipients, Characterization of physical, chemical and mechanical properties of new drug molecule in order to develop safe, effective , and stable dosage form. 25 August 2020 Krishna Pharmacy College, Bijnor 2

3. Preformulation is branch of Pharmaceutical science that utilizes biopharmaceutical principles in the determination of physicochemical properties of the drug substance. Prior to the development of any dosage form new drug , it is essential that certain fundamental physical & chemical properties of drug powder are determined . This information may dictate many of subsequent event & approaches in formulation development. This first learning phase is called as preformulation. 25 August 2020 Krishna Pharmacy College, Bijnor 3

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5. Objectives of preformulation studies To generate useful data needed in developing stable and safe dosage forms that can be manufactured on a commercial scale. To provide in-depth knowledge and understanding of the physical characteristics of a candidate drug molecule prior to dosage form development . To generate useful information on how to design a drug delivery system with good bioavailability . Preparation of safe, effective and stable dosage form with better therapeutic values. 25 August 2020 Krishna Pharmacy College, Bijnor 5

6. Goals of P reformulation studies To establish the physicochemical parameters of a candidate drug molecule. To determine the kinetic rate profile of drug substances. To establish the compatibility of a candidate drug molecule with common excipients. 25 August 2020 Krishna Pharmacy College, Bijnor 6

7. Classes of preformulation studies a. Fundamental preformulation studies: These studies are specific to candidate drug molecules and it include solubility analysis (e.g., ionization constant, partition coefficient, solubilization , thermal effect, common ion effect, dissolution etc.), solid state properties (e.g., polymorphism, solvated forms and amorphous form ), stability analysis (e.g., solution-state stability and solid-state stability) and permeability studies. These studies are dependent on the chemical structure of the candidate drug molecule. b. Derived preformulation studies: These studies include characterization of particle properties (e.g., particle size and particle shape), bulk density, powder flow properties, compaction behaviour etc. They are carried out on the intended dosage form . 25 August 2020 Krishna Pharmacy College, Bijnor 7

8. What to consider before starting a preformulation study Before embarking on preformulation studies, scientists must consider- The available physicochemical data including chemical structure, different salts, potency relative to the competitive products and the dosage form etc. Anticipated dose and the proposed route of drug administration. Supply situation and development schedule. Availability indicating assay . 25 August 2020 Krishna Pharmacy College, Bijnor 8

9. Evaluated parameters in preformulation studies a. Physical characteristics Organoleptic properties of the candidate drug molecule e.g., colour , odour and taste. Bulk characterization  e.g., particle size and surface area, powder flow properties, density, compressibility, crystallinity , polymorphism and hygroscopicity. Solubility analysis e.g ., ionization constant/ drug Pka , partition coefficient, solubilization , thermal effect, common ion effect ( Ksp ) and dissolution. Stability analysis  e.g., solution-state stability testing, solid-state stability testing, and drug-excipient compatibility studies . 25 August 2020 Krishna Pharmacy College, Bijnor 9

10. Continue… b. Chemical characteristics Hydrolysis Oxidation Reduction Racemization Polymerization Isomerization Photostability 25 August 2020 Krishna Pharmacy College, Bijnor 10

11. ORGANOLEPTIC CHARACTERS “Organoleptic properties are those properties which are evaluated after an impression on the organs of sense.” Colour,odour , taste of the new drug must be recorded. 25 August 2020 Krishna Pharmacy College, Bijnor 11

12. Colour Colour can be useful, while describing different batches of drug, it can sometimes be used as an indicator of solvent presence or more importantly of degradation. In addition minute difference in colour due to particle size distribution. Colour of various drug formulation may indicate the degradation process, the colour of certain types of formulation can be improved by adding certain dyes 25 August 2020 Krishna Pharmacy College, Bijnor 12

13. odour 25 August 2020 Krishna Pharmacy College, Bijnor 13

14. 25 August 2020 Krishna Pharmacy College, Bijnor 14

15. Physical form (crystal & amorphous) 25 August 2020 Krishna Pharmacy College, Bijnor 15

16. Different types of crystal 25 August 2020 Krishna Pharmacy College, Bijnor 16

17. Continue…… 25 August 2020 Krishna Pharmacy College, Bijnor 17

18. Difference between crystalline and amorphous form Crystalline form Amorphous form  Have fixed internal structure. Do not have any fixed internal structure. More stable than its amorphous forms. Less stable than its crystalline forms. Has lesser solubility than its amorphous form. Have greater solubility than its crystalline forms. Lesser tendency to change its form during storage. Tend to revert to more stable forms during storage. 25 August 2020 Krishna Pharmacy College, Bijnor 18

19. Continue…. 25 August 2020 Krishna Pharmacy College, Bijnor 19

20. Continue…. 25 August 2020 Krishna Pharmacy College, Bijnor 20

21. 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.  25 August 2020 Krishna Pharmacy College, Bijnor 21

22. Continue…. Polymorphs differ from each other with respect to their physical property such as Solubility Melting point Density Hardness Compression characteristic Eg . Chloromphenicol exist in A,B & C forms, of these B form is more stable & most preferable. 25 August 2020 Krishna Pharmacy College, Bijnor 22

23. Methods to identify polymorphism Optical crystallography Hot 0stage microscopy X- Ray Diffraction method NMR technique FTIR technique. Microcalorimetry Thermal methods Melting point determination 25 August 2020 Krishna Pharmacy College, Bijnor 23

24. PROPERTIES OF POLYMORPHS Polymorphs show the same properties in liquid or gaseous state but they behave differently in solid state. Polymorphs differ from each other with respect to physical properties like Melting and sublimation temperature Vapour pressure Solubility and dissolution rate Stability Optical and electrical properties Crystal habit Hygroscopicity Heat capacity Solid – state reactions Conductivity Compression characteristics 25 August 2020 Krishna Pharmacy College, Bijnor 24

25. Particle size and shape Not only effect only physical properties of solid drug but also, in some instances effect on the biopharmaceutical behavior Size, shape & surface morphology of drug particles affect Flow property Dissolution Chemical reactivity of drugs 25 August 2020 Krishna Pharmacy College, Bijnor 25

26. Significance of particle size Particle size of drug may affect formulation and product efficacy Particle size can influence variety of important factors The particle size Drug dissolution rate Content uniformity Texture Stability Flow characteristics Sedimentation rates Penetrability Suspendability Particle size significantly influences the oral absorption profile of certain drugs Satisfactory content uniformity in solid dosage forms depends to a large degree on particle size and the equal distribution of active ingredients throughout the formulation 25 August 2020 Krishna Pharmacy College, Bijnor 26

27. particle size continue….  Particle size is characterized using these terms : Very coarse, Coarse, Moderately coarse, Fine ,Very fine . 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) 25 August 2020 Krishna Pharmacy College, Bijnor 27

28. HOWEVER SIZE REDUCTION IS NOT REQUIRED IN FOLLOWING CASES When drug is unstable. D egrade in solution form. P roduce undesirable effects. W hen sustained effect is desired 25 August 2020 Krishna Pharmacy College, Bijnor 28

29. POWDER FLOW PROPERTIES Powder flow properties can be affected by change in particle size, shape & density. The flow properties depends upon following- Force of friction. Cohesion between one particle to another. Fine particle posses poor flow by filling void spaces between larger particles causing packing & densification of particles. By using glident we can alter the flow properties. e.g. Talc 25 August 2020 Krishna Pharmacy College, Bijnor 29

30. Determination of Powder Flow Properties By determining Angle of Repose. A greater angle of repose indicate poor flow. It should be less than 30°. & can be determined by following equation. tan θ = h/r. where , θ = angle of repose. h=height of pile. r = radius. 25 August 2020 Krishna Pharmacy College, Bijnor 30

31. Methods to determine angle of repose Static angle of repose Fixed-funnel method Fixed-cone method Kinetic or dynamic method Rotating cylinder method Tilting box method 25 August 2020 Krishna Pharmacy College, Bijnor 31

32. Determination of Powder Flow Properties 25 August 2020 Krishna Pharmacy College, Bijnor 32

33. 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 25 August 2020 Krishna Pharmacy College, Bijnor 33

34. solubility Solution phase equilibrium with solid phase at a stated temperature and pressure . Determines amount of drug dissolved , amount of drug available for absorption. Solubility reduction is carried out in certain conditions: Enhancement of chemical stability. taste masking products. Production of sustained release products. 25 August 2020 Krishna Pharmacy College, Bijnor 34

35. Continue…. The equilibrium solubility is based on the phase-solubility technique proposed by Higuchi-Connors. Method Drug dispersed in solvent in a closed container agitated at a constant temperature using shakers samples of the slurry are withdrawn as a function of time clarified by centrifugation and assayed by HPLC, UV, GC etc 25 August 2020 Krishna Pharmacy College, Bijnor 35

36. Continue…. It is important for orally administered drugs or drugs needed to be converted into solutions. It includes: pKa determinations pH solubility profile and common ion effects Effect of temperature Solubilization Partition coefficient Dissolution 25 August 2020 Krishna Pharmacy College, Bijnor 36

37. General Method of Increasing the Solubility Addition of co-solvent pH change method Reduction of particle size Temperature change method Hydotrophy Addition of Surfactant Dielectrical Constant Complexation 25 August 2020 Krishna Pharmacy College, Bijnor 37

38. p K a determination pKa is the dissociation constant of a drug The un-ionized drug is lipid soluble thus permeates through lipid membrane. The ionized substance is lipid insoluble therefore permeation is slow Degree of ionization depends on pH 25 August 2020 Krishna Pharmacy College, Bijnor 38

39. Continue…. It is important for drugs capable of ionization within a pH range (1-10), since solubility and then absorption can be changed by pH changes. As example, for a weakly acidic drug with pka value greater than 3, the unionized form is present within the acidic contents of the stomach, but the drug is ionized predominantly in the neutral media of the intestine. for basic drugs such as erythromycin, ( pka ˜ 8-9), the ionized form is predominant in both the stomach and intestine. 25 August 2020 Krishna Pharmacy College, Bijnor 39

40. Partition Coefficient Ratio of unionized drug distributed between the organic & inorganic aqueous phase at equilibrium. Importance Screening for biological Drug delivery System used are Octanol /water and Chloroform/water 25 August 2020 Krishna Pharmacy College, Bijnor 40

41. Methods of finding Partition coefficient: Shake-flask method Chromatographic method. Counter current and filter probe method. Tomlinson’s filter probe method. Micro electro-metric titratation method Automated instrument is now available. Applications of Partition coefficient: Measure of Lipophilic character of molecules. Recovery of antibiotics from fermentation broth. Extraction of drug from biological fluid for therapeutic monitoring. Absorption of drug from dosage forms. (Ointments, Suppositories, Transdermalpatches ). Study of distribution of flavouring oil between oil & water in emulsion. 25 August 2020 Krishna Pharmacy College, Bijnor 41

42. p H Solubility Profile & Common Ion Effects   Solubility of an acidic or basic drug depends on- pKa of the ionizing functional group & intrinsic solubilities for both the ionized & unionized forms . Experimental determination of a solubility product should include measurement of pH as well as assays of both drug & counter ion concentrations . 25 August 2020 Krishna Pharmacy College, Bijnor 42

43. Dissolution Dissolution  is an important step during preformulation studies because the rate of drug dissolution of a drug will exert a direct impact on bioavailability and drug delivery aspects (Bergstrom et al., 2014). Dissolution can be defined as the process through which drug particles tend to dissolve in the body fluids. Any change in drug dissolution will significantly affect the bioavailability. Dissolution of a drug particle is controlled by several physicochemical properties, including chemical form, crystal habit, particle size, surface area, solubility and wetting properties. 25 August 2020 Krishna Pharmacy College, Bijnor 43

44. Continue…. The modified Noyes–Whitney equation describes the drug dissolution in which surface area is constant during disintegration. Dc/ dt =DA/ hV x (CS−C) where, D =diffusion coefficient of the drug in the dissolution medium. h =thickness of the diffusion layer at the solid/liquid interface. A =surface area of drug exposed to dissolution medium. V =volume of the medium. C S =Concentration of saturated solution of the solute in the dissolution medium at the experimental temperature. C =Concentration of drug in solution at time  t . When  A =constant and  C S ≫ C 25 August 2020 Krishna Pharmacy College, Bijnor 44

45. Permeability Once in solution in physiological fluids  e.g.  gastric juices or plasma, a drug must permeate cells and tissues to reach its target site of action. This will involve passive and/or active transport mechanisms. For passive diffusion the drug will need to partition with the lipid components of cells and/or diffuse through aqueous pores in tissues. An index of its permeability can be obtained  in vitro  by measuring the permeability across a model membrane at a constant temperature, Typically the drug in solution is placed in one side of a two-compartment cell separated from the second compartment by a polymeric membrane, the second compartment containing a physiological representation fluid,  e.g.  normal saline. The amount of drug permeating through the membrane can be measured at various time intervals. A variety of membranes may be chosen each differing in their lipid composition . 25 August 2020 Krishna Pharmacy College, Bijnor 45

46. Hydrolysis Hydrolysis involves reaction of a molecule with water resulting in cleavage of a chemical bond within the molecule. If readily hydrolyzable functional groups are available, then reaction proceeds even at faster rates, making the molecule ineffective . Molecules containing esters and amide functional groups are prone to hydrolysis and especially the ester derivatives, which may lead to formation of carboxylic acid or an alcohol. 25 August 2020 Krishna Pharmacy College, Bijnor 46

47. Effectiveness of molecule therefore depends on hydrolytic stability of molecule. For example, lidocaine is amide derivative of procaine, which is ester derivative used as local anesthetic. As ester derivative is more readily hydrolyzed; its duration of action is short while amide derivative is more stable and hence used as long-acting local anesthetic. Beta-lactam antibiotics are susceptible to hydrolysis and hence they are supplied as dry powder injection where they are reconstituted before intravenous administration . Continue…. 25 August 2020 Krishna Pharmacy College, Bijnor 47

48. Factors to be considered in Hydrolysis pH Type of solvent : solvent lower dielectric constant Eg .: ethanol,glycols , mannitol etc. Complexation : steric or polar effects. Eg .: caffeine with benzocaine – electronic influence of complexing agent – alters affinity Surfactants : nonionic , cationic , anionic stabilizes drug against base catalysis. Eg : 5% SLS – 18folds increase in t1/2 of benzocaine Modification of chemical structure Salts and esters 25 August 2020 Krishna Pharmacy College, Bijnor 48

49. oxidation It is a very common pathway for drug degradation in liquid and solid formulations. Oxidation occurs in two ways 1. Auto- oxidation 2. Free radical chain process. Reaction of any material with molecular oxygen producing free radicals by hemolytic bond fission of a covalent bond. These radicals are highly unsaturated and readily accept electron from other substance causing oxidation is called Auto- oxidation . Free radical chain process involves Initiation , Propagation, Hydro peroxide decomposition and Termination. Factors affecting oxidation process are Oxygen concentration, light, heavy metals particularly those having two or more valence state (copper, iron, nickel, cobalt), hydrogen and hydroxyl ion, temperature. 25 August 2020 Krishna Pharmacy College, Bijnor 49

50. Continue…. Oxidation can be Prevented by Reducing oxygen content-oxidative degradation of drug takes place in an aqueous solution, so the oxygen content can be decreased by boiling water or by storing the formulation in in a dark and cool condition or by addition of an antioxidant/ reducing agent / chain inhibitors of radical induced decomposition. Antioxidants are of two types based on Solubility. Oil soluble and Water soluble. Oil Soluble Antioxidants are Free radical acceptors and inhibit free radical chain process eg : hydroquinone, propylgallate , lecithin whereas Water soluble Antioxidants Oxidizes itself and prevents oxidation of drug Eg : sodium metabisulphate , sodium bisulfate , thioglycolic acid, thioglycerol . 25 August 2020 Krishna Pharmacy College, Bijnor 50

51. Reduction Reduction is a relatively morecommon pathway of drug metabolic process. Hepatic microsomescatalyze diverse reductive chemical reaction * and require NADPHfor this purpose. Azo and nitro reduction is catalyzed by cytochrome P-450. Chloral hydrate is reduced to it’s active metabolite trichloroethanol by alcohol dehydrogenase . Reduction of prednisolone and cortisone results in the formation of their active metabolites hydrocortisone. Azo dyes used as coloring agents in pharmaceutical products or food are reduced to form amines in the liver and by the intestinal flora . 25 August 2020 Krishna Pharmacy College, Bijnor 51

52. Racemization It is an event where optically active molecule becomes inactive without any change in molecular composition. Such study is of highest importance when racemic mixture form is used. The interconversion from one isomer to another can lead to different P’cokinetic properties (ADME) as well as different P’cological & toxicological effect. Eg . L-epinephrine is 15 to 20 times more active than D-form, while activity ofracemic mixture is just one half of the L-form. It follows first order kinetics. It depends on temperature, solvent, catalyst & presence or absence of light . Racemization is mostly affected by the conditions like pH, type of solvents, presence of light, and temperature. So main goal in this study is to design optimum condition in which molecule can remain stable 25 August 2020 Krishna Pharmacy College, Bijnor 52

53. Polymerization It is a continuous reaction between molecules. More than one monomer reacts to form a polymer . Eg . Darkening of glucose solution is attributed to polymerization of breakdown product [5- (hydroxyl methyl) furfural]. Eg . Polymerization of HCHO to para -HCHO which crystallizes out from the solution. 25 August 2020 Krishna Pharmacy College, Bijnor 53

54. Photolysis Electronic configuration of drug overlaps with the spectrum of sunlight or any artificial light where energy is absorbed by the electron resulting in excitation . As they are unstable, they release the acquired energy and return to the ground state by decomposing the drug. The phenomenon where molecules or excipients which absorb energy but donot participate themselves directly in the reaction but transfer the energy to others which cause cellular damage by inducing radical formation is known as photosensitization. Photosentizer Convert oxygen from its ground state to singlet excited state and Generate superoxide molecule which is an anion radical and acts as a powerful oxidizing agents. 25 August 2020 Krishna Pharmacy College, Bijnor 54

55. Photo Decomposition Pathway N- dealkylation : eg:Dipenhydramine , Chloroquine , Methotrexate Dehalogenation : eg :- Chlorpropamide , Furesemide Dehydrogenation of ca ++ channel blockers Decarboxylation in anti-inflammatory drugs : Naproxen , Flurbiprofen , Benzoxaprofen Oxidation :- Chlorpromazine and other phenothiazines give n- oxides in the presence of sunlight. Isomerization and cyclization :-Noradrenaline , Doxapine Rearrangement : Metronidazole and oxidiazine yellow color Photodecomposition canbe Prevented by-suitable packing, antioxidant , protection of drug from light, avoiding sunbath, photostabilizer , coating 25 August 2020 Krishna Pharmacy College, Bijnor 55

56. Testing scope for Solid dosage ( Tablet & Capsule) Physical-chemical properties – Appearance Elasticity Mean mass Moisture Hardness Disintegration Dissolution Chemical properties – Assay Degradation Microbial properties Container closure system properties – Functionality tests (e.g. extraction from blister ) 25 August 2020 Krishna Pharmacy College, Bijnor 56

57. Testing scope for Oral liquid form Physical-chemical properties – pH Color & clarity of solution Viscosity Particle size distribution (for oral suspensions only) Chemical properties – Assay Degradation products Degradation preservatives Content antioxidants Microbial properties Container closure system properties Functionality tests 25 August 2020 Krishna Pharmacy College, Bijnor 57

58. Testing scope for LIQUID FORMS ( injection and PARENTRAL) Physical-chemical properties – pH Loss on weight Color & clarity of solution Chemical properties Assay Degradation products Degradation preservatives Content antioxidants Microbial properties Container closure system properties – Functionality tests 25 August 2020 Krishna Pharmacy College, Bijnor 58

59. Testing scope for ( SEMI LIQUID FORMS) Physical-chemical properties – Appearance , odor, homogenesity , consistency Loss on weight, Viscosity Content uniformity (within the container) Chemical properties – Assay Degradation products & preservatives Content preservatives Degradation-Content antioxidants Microbial properties Container closure system properties – Functionality tests 25 August 2020 Krishna Pharmacy College, Bijnor 59

60. Why stability analysis/ testing? To generate useful information on how environmental factors e.g., temperature, humidity, light etc. influence the quality of drug products over time. To establish the how physical, chemical and microbiological changes influence the effectiveness, safety and stability of the final drug product. To recommend storage conditions, establish a retest period, and shelf life of drug products 25 August 2020 Krishna Pharmacy College, Bijnor 60

61. Factors influencing drug stability Temperature or thermal effect Moisture and relative humidity Light and radiation energy pH Presence of reacting solvents Order of reaction Microorganisms Chemical nature of the drug or excipient Ionic strength General acid-base catalysis Presence of trace metals, oxygen, and oxidizing agents 25 August 2020 Krishna Pharmacy College, Bijnor 61

62. Significant changes that might occur during stability analysis Physical changes  – changes in the physical appearance of the drug product, melting point, clarity and color of solutions, crystal modification (polymorphism) and particle size, etc. Chemical changes  – increased degradation and decrease API (Active Pharmaceutical Ingredient) assay Microbial changes  – increased microbial load/ microbial contamination . 25 August 2020 Krishna Pharmacy College, Bijnor 62

63. Stability analysis Is usually the first quantitative assessment of chemical stability of a new drug. It includes both solution and solid state experiments under conditions typical for the handling, formulation, storage and administration of a drug candidate. Generally, it includes: Stability in toxicology formulations Solution stability Solid state stability 25 August 2020 Krishna Pharmacy College, Bijnor 63

64. Stability in toxicology formulations A drug is administered to the animal in their feed, or by oral gavage of a solution or suspension of the drug in an aqueous vehicle. Water, vitamins, minerals (metal ions), enzymes and a multitude of functional groups are present in feed, which can severely reduce the shelf- life of a drug. Solution and suspension formulations are checked for ease of manufacture and then stored in flame-sealed ampoules at various temperatures. 25 August 2020 Krishna Pharmacy College, Bijnor 64

65. Solution stability It is important for identification of conditions necessary to form a stable solution including the effects of (pH, ionic strength, co-solvent, light, temperature and oxygen). pH for maximum stability is determined using different types of buffers at constant conditions(?). Rate (K) Acid-base catalysis (pH rate profile) 25 August 2020 Krishna Pharmacy College, Bijnor 65

66. Ionic strength depends on the molar concentrations of ion (with valency), it must be constant specially for injectable solutions (about 0.15). Co-solvent can affect solubility and stability (hydrolysis prevention), solvents effects originated from dielectric constants values?, toxicity and compatibility. So the selected cosolvent must be selected at controlled conditions like (temperature not causes evaporation, sealing/packaging). The studies include photodegradation and oxidation depending on the drug, so if found (must be prevented ? how). 25 August 2020 Krishna Pharmacy College, Bijnor 66

67. Then, Arrhenius equation ? is used for studying the effect of temperature on solution at controlled conditions. The fractions of remaining drugs are assayed using UV, HPLC (the best?). After determination of the rate constant at 25°C, the shelf life can be calculated using the equation: t 10% = 0.105/K 25 Depending on the results, we can decide if, the drug can prepared in soluble, stable and effective form or not. 25 August 2020 Krishna Pharmacy College, Bijnor 67

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69. Solid state stability Includes identification of the suitable conditions for storage of solid drugs and drug-excipients compatibility. Solid state changes may include changes in the bulk properties.(so must be assayed as before) The reaction rates are much slower and more difficult to interpret.(why?) Generally, it involve placing of a new drug (certain weight) in open screw cap vials and then exposed directly to a variety of temperatures, humidities , and light intensities for long period of time. 25 August 2020 Krishna Pharmacy College, Bijnor 69

70. Effect of oxygen and light can be studied for effected drugs and then protected within study at various (T and RH). RH has its reaction rate constant (K H ), so as increased by increasing of water in atmosphere as the degradation increased. Solid drug-excipient compatibilities (physical or chemical ) must be evaluated using different assay methods for pure drug alone, physical mixtures (at certain ratio) and formulas. 25 August 2020 Krishna Pharmacy College, Bijnor 70

71. Purpose of stability study To ensure the efficacy. To ensure the safety. To ensure the quality of active drug substance and dosage forms. To establish shelf life or expiration period and to support label claims. To gain information about its packaging. Assess the condition of the product on storage on prolong period of time. To determine compatibility of drug with excipient and other additives. To determine the dosage form in which the drug is most suitable . 25 August 2020 Krishna Pharmacy College, Bijnor 71

72. BIOPHARMACEUTICS CLASSIFICATION SYSTEM   INTRODUCTION: The biopharmaceutics classification system is guidance for Predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration. The fundamental basis for the BCS was established by Dr. Gordon Amidon . DEFINITION: The Biopharmaceutical Classification System is a scientific framework for classifying a drug substance based on its aqueous solubility & intestinal permeability & dissolution rate 25 August 2020 Krishna Pharmacy College, Bijnor 72

73. OBJECTIVE OF THE BCS To improve the efficiency of the drug development and review process by recommending a strategy for identifying expendable clinical bioequivalence test. To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests. To recommend methods for classification according to dosage form dissolution along with the solubility– permeability characteristics of the drug product. 25 August 2020 Krishna Pharmacy College, Bijnor 73

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76. CLASSIFICATIAON According to the BCS, drug substances are classified as follows: A . CLASS I High Permeability and high Solubility. These are well absorbed and their absorption rate is usually higher than excretion. Drugs dissolved rapidly Drugs absorbed rapidly Rapid therapeutic action Excellent property Ideal for oral route Ex. Metoprolol , Diltiazem , Verapamil, Propranolol , 25 August 2020 Krishna Pharmacy College, Bijnor 76

77. Continue…. B. CLASS II High Permeability and Low Solubility. Bioavailability is limited by their solvation rate. Drugs dissolve slowly Drugs absorbed rapidly Controlled released drugs Oral / IV route for administration Ex. Glibenclamide , Ezetimibe , Phenytoin, Nifedipine . 25 August 2020 Krishna Pharmacy College, Bijnor 77

78. Continue…. C . CLASS III Low Permeability and High Solubility . Dissolved rapidly The absorption is limited by the permeation rate but drug is solvated very fast. Absorbance is limited Incomplete bioavailability Oral / IV route for administration Ex . Cimetidine, Acyclovir, Captopril 25 August 2020 Krishna Pharmacy College, Bijnor 78

79. Continue….. D. CLASS IV Low Permeability And Low Solubility. Poor bioavailability and Not well absorbed over the intestinal mucosa. Low dissolution rate Low permeability property Slow or low therapeutic action IV or other routes are required Example- Hydrochlorothiazide 25 August 2020 Krishna Pharmacy College, Bijnor 79

80. FACTOR AFFECTING ON BCS The Biopharmaceutical Classification System has been developed to provide a scientific approach to allow for to prediction in vivo pharmacokinetics of oral immediate release (IR) drug product by classifying drug compound based on their, SOLUBILITY PERMEABILITY DISSOLUTION 25 August 2020 Krishna Pharmacy College, Bijnor 80

81. Continue…. 1 . SOLUBILITY The Maximum Amount of solute dissolved in a given solvent under standard conditions of temperature, pressure and pH. Solubility is the ability of the drug to be solution after dissolution. The higher single unit dose is completely soluble in 250 ml at pH 1- 6.8 ( 37˚C ). 25 August 2020 Krishna Pharmacy College, Bijnor 81

82. Continue…. 2. PERMEABILITY Permeability of the drug to pass the biological membrane which is the lipophilic . Permeability is indirectly based on the extent of absorption of a drug substance. Drug substance is considered to be highly permeable, when the extent of absorption in human determined to be 90% or more of administered drug or compare to in vivo reference dose. 25 August 2020 Krishna Pharmacy College, Bijnor 82

83. Continue…. 3. DISSOLUTION A drug product is considered to be RAPIDLY DISSOLVING when > 85% of the labeled amount of drug substance dissolves within 30 minutes using USP dissolution apparatus I or II in a volume of 900 ml or less in the following media: 0.1 N HCl or simulated gastric fluid (pH 1.2) without enzyme. pH 4.5 buffer & pH 6.8 buffer. Simulated intestinal fluid without enzyme 25 August 2020 Krishna Pharmacy College, Bijnor 83

84. IVIVC - in vitro in vivo correlation IRP - immediate release product 25 August 2020 Krishna Pharmacy College, Bijnor 84

85. SIGNIFICANCE OF BCS It can save both time and money—if the immediate -release, orally administered drug meets specific criteria, the FDA will grant a waiver for expensive and time-consuming bio-equivalence studies. Valuable tool for formulation scientist for selection of design of formulated drug substance. When integrated with other information provide a tremendous tool for efficient drug development. Reduces cost and time of approving Scale- up and post approval challenges. Applicable in both pre-clinical and clinical drug development process. Works as a guiding tool in development of various oral drug delivery systems. 25 August 2020 Krishna Pharmacy College, Bijnor 85

86. Application of preformulation considerations Objectives of the Preformulation Considerations are- To provide and understand The degradation process, Any adverse conditions relevant to the drug, Bioavailability, Pharmacokinetics and formulation of similar compound and Toxicity 25 August 2020 Krishna Pharmacy College, Bijnor 86

87. Continue…. Usefulness of Preformulation Consideration- Selection of the drug candidate itself, Selection of formulation components, API & drug product manufacturing processes, Determination of the most appropriate container closure system, Development of analytical methods, Assignment of api retest periods The synthetic route of the api , Toxicological strategy . 25 August 2020 Krishna Pharmacy College, Bijnor 87

88. solid dosage forms development Solid dosage form acquires most of the pharmaceutical market. The typical parameter studies for solid dosage forms relate to the ability of a powder mix to flow well in manufacturing machines and to the intrinsic characteristics that make it compressible. Pre-formulation influences on selection of the drug candidate itself S election of formulation components, API & drug product manufacturing processes . D etermination of the most appropriate container closure system, development of analytical methods, assignment of API retest periods, the synthetic route of the API and toxicological strategy. 25 August 2020 Krishna Pharmacy College, Bijnor 88

89. Continue…. The most important function of pre-formulation stage is solid state characterization which determines the next step in the formulation work of the studied API. Solubility studies identify those drugs with a potential for bioavailability problems. E.g. Drug having limited solubility (7 %) in the fluids of GIT often exhibit poor or erratic absorption unless dosage forms are tailored for the drug. Physical properties of the studied API influence on its physical and chemical stability.  A drug for oral administrative should be examined for solubility in an isotonic saline solution and acidic pH. This solubility data may provide the dissolution profile in vivo . 25 August 2020 Krishna Pharmacy College, Bijnor 89

90. Continue . . . . It influences on the rout of administration, delivery system and the drug activity. Moreover, Chemical stability of the drug is affected by the physical properties. Crystal morphology, polymorphism, amorphous forms and hygroscopicity are usually studied. In addition, solubility, salt form, melting point, dissolution of the API are also studied. 25 August 2020 Krishna Pharmacy College, Bijnor 90

91. Liquid dosage form development After solid dosage form second largest market is of liquid dosage form. Liquid dosage form has certain advantages like easy administration, fast absorption and variety of dosage form like syrup, emulsion, suspension etc. During development of liquid dosage form formulation of type of dosage form is based on preformulation studies, if drug is aqueous soluble then it can be easily formulated in solution dosage form, if drug is insoluble then it can be formulated in suspension form, oily drug can be formulated in emulsion form. 25 August 2020 Krishna Pharmacy College, Bijnor 91

92. Continue . . . . Solubility in various mediums is useful in developing suspension or solution toxicological and pharmacological studies. Characterization of drug in solid form for particle size and surface area during formulation of liquid dosage form is also important as it affect various parameters of liquid dosage form. Stability concern is more in liquid dosage form as compared to solid dosage form, as liquid provides media for various degradation processes hence special concern should be provided over stability in case of liquid dosage form. Selection of container closure system is also important criteria during preformulation of liquid dosage form. 25 August 2020 Krishna Pharmacy College, Bijnor 92

93. Continue . . . . Some of the examples studied during liquid preformulation studied include organoleptic characters like taste, colour, viscosity and flow ability studies, stability studies, solubility of API, selection of vehicle and proper excipients like preservatives, antioxidants etc. 25 August 2020 Krishna Pharmacy College, Bijnor 93

94. Parenteral dosage form development Parenteral word means outside of intestine. The drugs which are injected into the body come under parenteral. Preformulation studies of parenteral dosage forms include bulk characterization like particle size, powder flow properties, crystallinity and polymorphism, solubility study including pka determination, partition coefficient, stability study, spectroscopic studies, microscopic studies, chromatographic studies. Selection of container closure system is also important criteria during preformulation studied of parenteral dosage form. 25 August 2020 Krishna Pharmacy College, Bijnor 94

95. conclusion Preformulation studies have a significant part to play in anticipating formulation problems and identifying logical path in both liquid and solid dosage form technology. The need for adequate drug solubility cannot be overemphasized. The most appropriate salt for development. Stability studies in solution will indicate the feasibility of parental or other liquid dosage form and can identify methods of stabilization. In parallel solid-state stability by DSC, TLC and HPLC in the presence of tablet and capsule excipient will indicate the most acceptable vehicles for solid dosage form. This review article gives details of above studies with respect to any sustained release dosage forms can be developed without preformulation studies. 25 August 2020 Krishna Pharmacy College, Bijnor 95

96. References https:// www.pharmapproach.com/preformulation-studies https:// www.slideshare.net/makoye1954/preformulation-studies-62541046 vnd.mspowerpoint preformulation studies-1 https:// www.slideshare.net/Protik007/preformulation-60288468 https:// www.slideshare.net/makoye1954/preformulation-studies-62541046 https:// www.researchgate.net/publication/324819639_Preformulation_lecture-1/link/5ae43186a6fdcc3bea943cd7 https://www.intechopen.com/books/pharmaceutical-formulation-design-recent-practices/preformulation-studies-an-integral-part-of-formulation-design https://www.researchgate.net/publication/330193840_AN_OVERVIEW_ON_PREFORMULATION_STUDIES https://www.slideshare.net/venkateshdaggumati/1-preformulation https://www.pharmapproach.com/preformulation-studies-stability-analysis/ 25 August 2020 Krishna Pharmacy College, Bijnor 96

97. continue.… https :// www.ijptonline.com/wpcontent/uploads/2009/10/2311-2331.pdf http:// www.ijpacr.com/files/07-04-2017/34.pdf https:// www.researchgate.net/publication/286453649_Preformulation_Studies_of_Pharmaceutical_New_Drug_Molecule_Products_An_Overview https:// www.slideshare.net/sagarsavale1/bio-pharmaceutical-classification-system-bcs https ://www.slideshare.net/azkagull1/skb-bcs-presentation https:// www.slideshare.net/PrinceDivyesh/biopharmaceutics-classification-system-80736223 https:// www.longdom.org/conference-abstracts-files/2153-2435.S1.025-074.pdf https:// www.slideshare.net/ImranNurManik/preformulation-considerations-ppt https://www.slideshare.net/SarojMakwana/preformulation-80763095 25 August 2020 Krishna Pharmacy College, Bijnor 97

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