PREFORMULATION

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PREFORMULATION presented by SUNILBOREDDY 1

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contents 1.Concept of preformulation 2.Steps in preformulation process 3.Physicochemical properties 4.Solubility 5.pKa determinations 6.Partition coefficient 7.pH- solubility profile 8.Prodrug approach 9.Polymorphism 10.Conclusion references 2

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THE CONCEPT OF PREFORMULATION:- Almost all drugs are marketed as tablets, capsules or both. Prior to the development of these major dosage forms, it is essential that certain fundamental, physical and chemical properties of the drug molecule and other properties of the drug powder are determined. This information decides many of the subsequent events and approaches in formulation development. This first learning phase is known as preformulation Definition:- It can be defined as an investigation of physical and chemical properties of a drug substance - alone and or when combined with excipients . The overall objective of preformulation testing is to generate information useful to the formulator in developing stable and safe dosage forms with good bioavailability. 3

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During the early development of a new drug substance, the synthetic chemist, alone or in cooperation with specialists in other disciplines (including preformulation), may record some data which can be appropriately considered as preformulation data . This early data collection may include such information as - Gross particle size, - Melting point, - Infrared analysis, - Thin-layer chromatographic purity, - And other characteristics . These data are useful in guiding, and becoming part of, the main body of preformulation work. 4

Steps in Preformulation Process Pharmaceutical Research:

5 Steps in Preformulation Process Pharmaceutical Research 1. Stability i. Solubility a. Solid State (1) Water and Other Solvents (1) Temperature (2) pH-Solubility Profile (2) Light (3) Salt Forms (3) Humidity (4) Co solvents b. Solution (5) Complexation (1) Solvent (6) Prodrug (2) pH j. partition coefficient (3) Light k. polymorphism potential 3. Physico-mechanical Properties a. Bulk and Tapped Density 2. Physico-chemical Properties b. Compressibility a. Molecular Structure and Weight b. Color c. Odor d. Particle size, Shape, and Crystallinity e. Melting Point 4 . In Vitro Availability Properties f. Thermal Analysis Profile a. Dissolution of Drug Crystal Per sec (1) DTA b. Dissolution of Pure Drug Pellet (2) DSC c. Dissolution Analysis of Pure Drug (3) TGA g. Hygroscopicity Potential 5. Other Studies h. Absorbance Spectra a. Plasma Protein Binding (1) UV b. Effect of Compatible Excipients (2) IR on Dissolution c. Kinetic Studies of Solution Degradation

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Particle Size, Shape and Surface Area:- Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes .The effect is not only on the physical properties of solid drugs but also, in some instances, on their biopharmaceutical behavior .It is generally recognized that poorly soluble drugs showing a dissolution- rate limiting step in the absorption process will be more readily bio available when administered in a finely subdivided state rather than as a coarse material. In case of tablets, size and shape influence the flow and the mixing efficiency of powders and granules. Size can also be a factor in stability . Fine materials are relatively more open to attack from atmospheric oxygen, the humidity, and interacting excipient than are coarse materials. 6 Physicochemical properties

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Effects of particle size and shape on: - Chemical and physical properties of drug substances. - Bioavailability of drug substances(Griseofulvin,Chlorpropamide). - Flow and mixing efficiency of powders and granules in making tablets. - Stability, fine materials relatively more open to attack from atmospheric O 2 , heat, light, humidity, and interacting excipients than coarse materials. 7

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Very fine materials are difficult to handle, overcome by creating solid solution in a carrier (water-soluble polymer). Important to decide, maintain, and control a desired size range. Safest - grind most new drugs with particle diameter > 100 m m (~ 140 mesh) down to ~ 10 - 40 m m (~ 325 mesh) . Particles with diameter < 30 m m (~ 400 mesh) , grinding is unnecessary except needle-like to……. improve flow. Drawbacks to grinding: - Material losses. - Static charge build-up. - Aggregation => Lowering dissolution rate. - Polymorphic or chemical transformations. 8

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General Techniques For Determining Particle Size Microscopy - Most rapid technique. - But for quantitative size determination requires counting large number of particles. - Suspending the material in non dissolving fluid (water or mineral oil) Particle size and shape can be determined by using optical microscope , polarizing microscope or by scanning electron microscope (SEM).The data recorded either by a sketch or more accurately by a photomicrograph . Polarizing microscope is used to determine whether a compound is crystalline or amorphous . Crystalline structures are visible (Refract the polarized light). Amorphous are invisible 9

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Crystal habit and internal structure of a drug can affect bulk and physicochemical properties , which range from flowability to stability . Habit is the description of the outer appearance of the crystal where as internal structure is the molecular arrangement with in the solid . Crystal habit types : Tabular : moderate expansion of two parallel faces ; Platy : excessive plate like development ; Prismatic : columnar form ; Acicular : needle like structure ; Bladed : flattened acicular . In internal structure of a compound the major distinction is whether the solid is crystalline or amorphous . 10

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Common Crystal Habits Habit Description Example Acicular Needle-like, slender(very narrow), and/or tapered quartz Bladed Blade-like, slender, and flattened Kyanite Columnar Similar to fibrous: long, slender prisms often with parallel growth Calcite Fibrous or columnar Extremely slender prisms Tremolite Filiform or capillary Hair-like or thread-like, extremely fine Natrolite Granular Aggregates of anhedral crystals in matrix Scheelite Prismatic Elongate, prism-like: all crystal faces parallel to c-axis Tourmaline 11

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MELTING POINT :-  Defined as the temperature at which the solid and liquid phases are in equilibrium . the melting point of a drug can be measured using three techniques:- 1) Capillary melting 2) Hot stage microscopy 3) Differential scanning calorimetric or thermal analysis. Capillary melting :- Capillary melting gives information about the melting range but it is different to assign an accurate melting point. Hot stage microscopy:- This the visual observation of melting under a microscope equipped with a heated and lagged sample stage. The heating rate is controllable and up to three transitions can be registered. These values are more accurate .    Differential scanning calorimetric and thermal analysis :- Differential thermal analysis (DTA) measures the temperature difference between the sample and a reference as a function of temperature or time when heating at a constant rate . Differential scanning calorimetric (DSC) is similar to DTA except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference . 12

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THERMAL ANALYTICAL PROFILE : Differential Scanning Calorimetry (DSC) and Differential Thermal Analysis (DTA) measure the heat loss or gain resulting from physical or chemical changes within a sample as a function of temperature . Examples of endothermic ( heat absorbing) process are. Fusion Boiling Sublimation Vaporization Solid solid transitions and chemical degradation . exothermic process are crystallization ,degradation . 13

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acyclovir Ethylcellulose film DSC thermograms of pure acyclovir and pure ethylcellulose films DSC thermograms of ethylcellulose film containing 12.8 % acyclovir with 15 % propylene glycol and 10 % Tween 80 14

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HYGROSCOPICITY Many drug substances , particularly water soluble salt forms have a tendency to adsorb atmospheric moisture . adsorption can depend upon the humidity temperature surface area mechanism for moisture uptake . The changes in moisture level can greatly influence many important parameters , such as chemical stability , flow ability and compatibility . PROCEDURE : To carry out a study , samples are accurately weighed in a tarred containers and placed at various humidity conditions for periods up to 2 weeks. Weight gain or loss is measured at predetermined time intervals until equilibrium is reached . If the drug is very hygroscopic or unstable in the presence of moisture , the drug would have to be stored under dry conditions . High hygroscopicity is undesirable for many reasons, including Handling problems, requirement of special storage conditions, chemical and physical stability problems. 15

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Solubility Determination:- The solubility of drug is an important physicochemical property because it affects the bioavailability of the drug, the rate of drug release into dissolution medium and consequently, the therapeutic efficiency of the pharmaceutical product. The solubility of the molecules in various solvents is determined as a first step. This information is valuable in developing a formulation. Solubility is usually determined in variety of commonly used solvents and some oils if the molecules are lipophillic.   The solubility of 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 until equilibrium achieved Solubility > 1 % w/v => no dissolution-related absorption problem 16

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The United States Pharmacopeia Solubility Classification Descriptive term Parts of solvent required for one part of solute Very soluble Less than 1 Freely soluble From 1 to 10 Soluble From 10 to 30 Sparingly soluble From 30 to 100 Slightly soluble From 100 to1000 Very slightly soluble From 1000 to10,000 Practically insoluble or insoluble 10,000 and over Common solvents used for solubility determination are:- Water ,Polyethylene Glycols ,Propylene Glycol ,Glycerin ,Sorbitol Ethyl Alcohol ,Methanol ,Benzyl Alcohol ,Isopropyl Alcohol ,Tweens ·Polysorbates ·Castor Oil ·Peanut Oil oils ·Sesame Oil ·Buffer at various pHs 17

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Solvent (fixed volume) Adding solute in small incremental amounts Vigorously shaking Undissolved solute particles ? Examine visually Yes No Total amount added up Estimated solubility Semiquantitative determination: Determination of Solubility… 18

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Excess drug powder 150 mg/ml (15 %) + solvent Ampule /vial (2-5 ml) Shaking at constant temperature (25 or 37 o C) or (2 - 8 o C ) The first few ml ’ s of the filtrates should be discarded due to possible filter adsorption 48 hr Membrane filter 0.45 m m Same concentration 72 hr Membrane filter 0.45 m m Membrane filter 0.45 m m Determine the drug concentration in the filtrate Determine the drug concentration in the filtrate Determine the drug concentration in the filtrate >72 hr Solubility Accurately Quantitative determination: 19

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PKa Determination:- 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 orders of magnitude with 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]) For a weakly acidic drug with pKa value greater than 3 , the un ionized form is present within the acidic contents of the stomach , but the drug is ionized in the neutral media of the intestine . For basic drugs such as erythromycin and papaverine pKa 8-9 the ionized form predominant in both the stomach and intestine . Buffer ,temperature , ionic strength and co solvent affect the pKa value . 20

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Partition Coefficient :- Partition Coefficient (oil/ water) is a measure of a drug’s Lipophillicity and an indication of its ability to cross cell membranes. It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium. P o/w = (C oil / C water) equilibrium. The partition coefficient can provide an empiric handle in screening for some biologic properties. For drug delivery, the lipophilic / hydrophilic balance has been shown to be a contributing factor for the rate and extent of drug absorption. Although partition coefficient data alone does not provide understanding of in vivo absorption, it does provide a means of characterizing the lipophilic/ hydrophilic nature of the drug . Since biological membranes are lipoid in nature. The rate of drug transfer for passively absorbed drugs is directly related to the Lipophillicity of the molecule. The partition coefficient is commonly determined using an oil phase of octanol or chloroform and water. Drugs having values if P much greater than 1 are classified as lipophilic, whereas those with partition coefficient much less than 1 are indicative of a hydrophilic drug. 21

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pH-Solubility Profile Excess drug powder Stir in beaker with distilled water Continuous stirring of suspension Add acid/base Measure pH of suspension Determine the concentration of drug in the filtrate SOLUBILITY pH Filter Stirring 22

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SALTS A major improvement in solubility can be achieved by forming a salt . A salt is a chemical combination of two ionizable components one acidic and one basic relative to the other . Either the acidic or basic moiety may be the drug . If pKa (acid) and pKa (base) are too close a stable salt may not form . Some molecules do not form salts , such as those do not dissociate when dissolved in water examples are steroids and alcohols . Among cations, the most frequently found ion is sodium (62%), followed by potassium and calcium (10%); zinc and magnesium (3%),lithium, magnesium , di ethanolamine, benzathine, ethyldiamine, aluminum, Chloro procaine, and choline (in decreasing order of frequency). 23

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Among anions, the most frequently used counter ion is hydrochloride (almost 50%), followed by sulfate(8%), bromide and chloride (5%), Di phosphate, citrate, maleate (3%), Iodine mesylate, hydro bromide (2%), acetate, pamoate (1%), isothionate, methylsulfate,salicylate, lactate, methyl bromide, nitrate, bitartrate, benzoate, dihydrochloride, gluconate, carbonate, edisylate, mandelate, methylnitrate, subacetate, succinate,benzenesulfonate, calcium edentate, camsylate, edentate, fumarate, glutamate, hydro bromine, napsylate, pantothenate, stearate, gluceptate, bicarbonate, estolate,esylate, glycollylarsinate, hexylresorcinate, lactobionate, maleate, mucate, polygalactoronate,teoclate, and triethiodide (in decreasing order of frequency). 24

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ACID pKa Acetate 4.76 Ascorbate 4.21 Benzoate 4.20 Besylate 2.54 Citrate 3.13 Fumarate 3.0, 4.4 Gluconate 3.60 Hydro bromide 8.0 Hydrochloride 6.1 Malate 3.5, 5.1 Mesylate 1.92 Napsylate 0.17 Oleate 4.0 Phosphate 2.15, 7.20, 12.38 Succinate 4.2, 5.6 Sulfate 3.0 Tartrate 3.0, 4.3 Tosylate 0.51 The pKa values of weak acids that are most frequently used in salt formation. 25

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A process flow for the selection of the best salt form 26

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NSAID’s aclofenac, diclofenac, fenb r ufen, ibuprofen, naproxen Weak acid pK a ~ 4, low solubility Salt forms sodium N-(2-hydroxy ethyl) piperazinum arginium N-methylglucosammonium Solubility diclofenac (free acid) : 0.8 mg/ml (37 o C) diclofenac sodium :24.5 mg/ml (37 o C) 27

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Quinolones enoxacin, norfloxacin, ciprofloxacin Salt forms lactate, acetate, gluconate, galacturonate, aspartate, glutamate, etc. Solubility Free base : < 0.1 mg/ml (25 o C) Salt forms : > 100 mg/ml (25 o C) 28

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COSOLVENTS Co solvents are used to solubilize the drug substance when its aqueous solubility alone is insufficient to achieve the desired level . The most widely used co solvent system is water/ethanol blend . Other suitable solvents are used with water include Sorbitol , glycerol , propylene glycol and syrup . Example a blend of propylene glycol and water is used to improve the solubility of co-trimoxazole in oral solutions . SOME PRODUCTS CONTAING CO SOLVENTS NAME CO SOLVENT COMPOSITION Dimenhydrinate 50% propylene glycol Hydralazine HCL 10% propylene glycol Multivitamin infusion 30% propylene glycol Pentobarbital sodium 40% propylene glycol , 10% ethanol Digoxin 40% propylene glycol , 10% ethanol Dihydroergotamine mesylate 6.1%ethanol , 15% glycerin Reserpine 10% dimethyl acetamide , 50% polyethylene 29

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Complexation Complexation can be analyzed and explained on the basis of “law of mass action” as follows: D (solid) D (solution) xD + yC D x C y S t = [D] + x[D x C y ] where D = drug molecule C = complexing agent (ligand) S t = total solubility of free drug [D] and the drug in the complex [D x C y ] 30

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A complex is an entity formed when two molecules , such as a drug and a solubilizing agent (ligand) are held together by weak forces . For complex formation to occur , drug and ligand molecules should be able to donate or accept a pair of electrons . LIGANDS OR COMPLEXING AGENTS…. Example………………….. Complex formation between the drug benzocaine and ligand caffeine can be attributed to the dipole dipole interaction between a partial negative charge on carboxy oxygen of benzocaine and a partial positive charge on nitrogen of caffeine . Vitamin K - Caffeine Menadione - Benzoic acid Cholesterol - PEG series - PVP - b -cyclodextrin 31

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PRODRUG APPROACH The term prodrug was first used by Albert and was defined as a compound that undergoes biotransformation prior to eliciting a pharmacological response . The Antiviral agent ara-A has a low aqueous solubility . The formate ester of ara-A was reported to be 66times more soluble in water than was ara-A. Some examples of water soluble prodrugs PARENT DRUG PRODRUG Oxazepam oxazepam sodium succinate Prednisolone prednisolone sodium succinate Prednisolone prednisolone disodium phosphate Parent corticosteroids hydrocortisone betamethasone methyl prednisolone dexamethasone Tetrahydrocannabinol tetrahydrocannabinol di sodium phosphate 32

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Polymorphism A compound may be amorphous or crystalline, where the compound has more than one crystalline form it is said to be exhibit polymorphism. Polymorphisms generally have Different melting points ,X-Ray diffraction patterns and solubility even though they are chemically identical. Although a drug substance may exist in two or more polymorphic forms, only one form is thermodynamically stable at a given temperature and pressure. In general the stable polymorph exhibits the highest melting point, the lowest solubitlity, and the maximum chemical stability. Various techniques are available for investigation of the solid state includes microscopy (hot stage microscopy) infrared spectrophotometry thermal analysis and X-Ray power diffraction. Chemical stability and solubility changes due to polymorphism can have an impact on drugs bioavailability and its development program. Polymorphism can be classified into 2 types. 33

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Enantiotropic: One polymorph can be reversibly changed into another by varying temperature and pressure. Ex: sulfur Monotropic: One polymorphic form is unstable at all temperatures and pressures. Ex: glyceryl stearates. During preformulation it is important to Identify the polymorph that is stable at room temperature Determine whether polymorphic transitions are possible within the temperature range used for stability studies and during processing. A more difficult task in the study of polymorphism is determination of relative stability of metastable polymorph and prediction of its rate of conversion with in dosage form. Some examples of drugs exhibiting polymorphism 1. Chloramphenicol palmitate Three crystalline forms (A, B, C) and amorphous Polymorphism A-inactive, polymorphism B-The more soluble form Pseudo polymorphism Pseudo polymorphs should be identified since most polymorphs can be obtained by changing the recrystallizing solvent. Solvents including polymorphic change are: water, methanal, ethnol, acetone,n-butonol,n-pentonal,benzene and toluene. 34

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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 most appropriate salt development and Stability studies in solution will indicate the feasibility of parental or other liquid dosage form and can identify methods of stabilization. By comparing the physicochemical properties of each drug candidate with in a therapeutic group, the preformulation scientist can assist the synthetic chemist to identify the optimum molecule, provide the biologist with suitable vehicles to elicit pharmacological response and advise the bulk chemist about the selection and production of the best salt with appropriate particle size and morphology for subsequent processing. 35

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References: 1.Leon Lachman , Herbert A lieberman,The theory and practice of industrial pharmacy 2009. 2.G. Banker and C.T. Rhodes, Modern Pharmaceutics, Marcel Dekker, Inc., 2000. 3.H. Brittain , Physical Characterization of Pharmaceutical Solids, Marcel Dekker, Inc., 1995. 4. H. Brittain , Polymorphism in Pharmaceutical Solids, Marcel Dekker, Inc., 1999. 5.S.R. Byrn , R.R. Pfeiffer and J.G. Stowell , Solid State Chemistry of Drugs, Second Edition, SSCI, Inc.,1999. 6.M. Gibson, Pharmaceutical Preformulation and Formulation, HIS Health Group, Englewood, CO, 2001. 7.D.J.W. Grant and T. Higuchi, Solubility Behavior of Organic Compounds, John Wiley & Sons, Inc., 1990. 8.L.J. Ravin and G.W. Radebaugh , “Preformulation”, Chapter 75 in Remington’s Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pennsylvania, 1990. 9.S. Yalkowsky , Solubility and Solubilization in Aqueous Media, American Chemical Society, Washington D.C. 1999. 10. Aulton’s pharmaceutics. The design and manufacture of medicines.2009. 36

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THANK YOU. 37

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