Preformulation and Production Managment by Kailash Vilegave

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Preformulation stability studies, physicochemical parameters affecting preformulation,need and objective of preformulation

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PREFORMULATION STUDIES A SEMINAR ON PREFORMULATION STUDIES OF NEW DRUG MOLECULE Presented by: Kailash V. Vilegave K.L.E.s COP Hubli 580031 Dept: Pharmaceutics Presented to: Smt. F. S. Dasankoppa Dept: Pharmaceutics K.L.E.s COP Hubli 580031 Respected, 1

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PREFORMULATION STUDIES Preview to Preformulation Introduction, Objectives & Goals, Entry of dosage form for marketing 2

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PREFORMULATION STUDIES Introduction - Evolved in 1950 & early 1960 Defination : As “an investigation of physical & chemical properties of drug substance alone and when combined with excipients” “ Preformulation involves the application of biopharmaceutical principles to the physicochemical parameters of drug substance are characterized with the goal of designing optimum drug delivery system”. “Prior studies taken before the formulations of various dosage forms” - “A step in time saves nine” So the Preformulation study of the new product can away the disaster i.e. disasters are prevented in advance Many people take various dosage forms without any hesitation about its safety ,….. why?...... because they trust on us & our formulations so we (Pharmaceutical scientist & formulation pharmacist) have also responsibility to go true to there expectations . i.e. development of a final product submitted to the FDA for marketing approval is promising one (withstand in chemical & physical properties) 3

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PREFORMULATION STUDIES Need of Dosage forms To provide mechanism for the safe & convenient delivery of accurate dose . To protect from environment i.e. destructive effect of oxygen or humidity. To protect from the destructive effect of gastric acid after oral administration Ex….Enteric coated tablet. To conceal the bitter, salty, nauseous odour of drug subt. Ex…..Capsule , Coated tablet . To provide liquid preparation which are unstable or insoluble in vehicle. Ex….Suspension To provide clear dosage forms of substance. Ex…..Syrups , Solutions To provide rate controlled drug action. Ex…..S.R. & C.R. Tablets To provide optimal drug action from topical administration. Ex……Oint., Creams, Patches. 4

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PREFORMULATION STUDIES Objectives To develop the elegant dosage forms (stable, effective & safe) It is important to have an understanding of the physical description of a drug subt before dosage form development. It is 1 st step in rational development of a dosage form of a drug subt before dosage form development . It generate useful information to the formulator to design an optimum drug delivery system. Goals To establish the physico -chemical parameters of new drug subt . To establish the physical characteristics. To establish the kinetic rate profile . To establish the compatibility with the common excipients. 5

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Entry of Dosage Form for marketing Drug synthesized Tested for pharmacolological activity Toxicity studies Analytical work Preformulation studies Actual formulation is done Phase 2 & 3 clinical trials NDA submitted report to the concerned authority Production started Marketing Approval by the FDA Final formula is finalized 6 PREFORMULATION STUDIES

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PREFORMULATION STUDIES MAJOR AREA OF PREFORMULATION RESEARCH Bulk characterization Crystallinity & polymorphism, Hygroscopicity, Fine particle characterization, Powder flow properties. 2. Solubility analysis Ionization constant –Pka pH solubility profile, Common ion effect-Ksp , Solubilization , Dissolution, Partition co-efficient. 3.Stability analysis Solution stability, pH rate profile, Solid state stability, Bulk stability, Stability in toxicology formulation . 7

CRYSTALLINITY & POLYMORPHISM:

PREFORMULATION STUDIES CRYSTALLINITY & POLYMORPHISM Crystal habit & internal structure of drug can affect physico-chemical properties which ranges from flow ability to chemical stability. Habit means the description of outer appearance of a crystal. While internal structure describes the molecular arrangement within the solid, changes in internal structure usually alter crystal habit. E.g. 1 : Conversion of sodium salt to its free acid form produce both a change in internal structure & crystal habit. Sodium salt Free acid E.g. 2 : Conversion of Sod. Benzoate to Benzoic acid. Sod. Benzoate Benzoic acid 8

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PREFORMULATION STUDIES CHEMICAL COMPOUND Habit Internal structure Crystalline Amorphous Polymorphs Molecular adduct Nonstoichiometric Inclusion compound Stoichiometric Solvates ( Hydrates) Channel Layer Cage Enantiotropic Monotropic 9

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PREFORMULATION STUDIES 10

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PREFORMULATION STUDIES Depending upon internal structure of a compound can be classified as A. Crystalline; B. Amorphous / non crystalline A. Crystalline: Crystals are characterized by repetitious spacing of constituent atoms or molecule in a dimensional array. Evaluation of crystal structure, polymorphism, & solvate form is an important Preformulation activity. The changes in crystal characteristics can influence bioavailability, chemical and physical stability, & can have implication in dosage form process functions. 11

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PREFORMULATION STUDIES B. Amorphous / non crystalline: In this form atoms or molecule are randomly placed as liquid. Ex. It can be a significance factor relating to tablet formulation because of flow and compaction behavior among other. 12

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PREFORMULATION STUDIES Polymorphism An important factor affect on formulation is the crystalline or amorphous form of the drug. Polymorphic form exhibits different physico-chemical properties including MP and solubility. Polymorphic form in drug are relatively common, it has been estimated that at least 1/3 of all organic compounds exhibit polymorphism. Defination: The property of drug that exist in more than one crystalline form that different forms are designated as polymorphs and its phenomenon is known as ‘Polymorphism ’ Types: 1) Enantiotrophic polymorphs, 2) Monotrophic polymorphs . ( Crystal forms) 13

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PREFORMULATION STUDIES 1 ) Enantiotrophic polymorphs: is the one which can be reversibly changed into another form by altering the temperature or pressure. Ex: Sulfur. Carbon . Nitrogen .Oxygen One form another form Pressure 2) Monotrophic polymorphs. The transition take place in only one direction is called as monotrophic polymorphs OR is one which is unstable at all tempt & pressure . Ex: glyceryl sterates. The polymorphs differ from each other with respect to there physical properties , such as solubility, MP, density, hardness, dissolution, compression characteristics. 14

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PREFORMULATION STUDIES Crystal morphology ‘Repetition of atom or molecule in regular thee dimensional array ( structure) There are six crystalline systems, 1) Cubic 2) Tetragonal 3) Orthorhombic 4) Monoclinic 5) Triclinic 6) Hexagonal Which have different internal structure & spatial arrangements. 15

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PREFORMULATION STUDIES 1) Tabular : moderate expansion of two parallel faces 2) Platy : plates 3) Prismatic : columns 4) Acicular : needle like 5) Bladed : flat acicular. Acicular Bladed As the change in internal structure there may be change in external structure i.e. crystal habit …… Of which five types are recognized Platy 16

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PREFORMULATION STUDIES 17

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PREFORMULATION STUDIES Crystal habit can be modified by…. ….. Excessive super saturation which tends to transform a prism to needle shape . ……Cooling rate & agitation which changes habit , it changes the degree of super saturation Ex. . Naphthalene gives thin plates when rapidly recristallized in cold Ethanol or Methanol …..The addition of co-solvent or other solutes & ions which change habit by poisoning crystal growth in one or more direction. Ex.. Sod. Chloride is cubic but Urea produces an octahedral habit. 18

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PREFORMULATION STUDIES POLYMORPHS ( DRUGS AND THERE POLYMORPHIC FORMS ) Steroids like Progesterone has 5 polymorphs. Barbiturates like Barbitone has 2,& Pentabarbitone has 3. Sulphonamides like Sulphabenzamide has 4 polymorphs & 3 solvates . Caffeine has 2 , Chlorpropamide has 3 Clenbuterol has 2 Dipyridamol has 2 Mebendazole has 4 Nadoxidine has 4 , Sulphabenzamide has 2 Phenobarbitone has 2 Sorbotol has 5 and Insulin 19

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PREFORMULATION STUDIES Effects of polymorphs Depending upon there chemical stability,& solubility changes due to polymorphism can impact on bioavailability Such form are… a) Stable polymorphs.& b) Metastable polymorphs a) Stable Polymorphs One of the several polymorphic forms will be physically more stable than the other. Such a stable polymorphs represents lowest energy state, has highest MP,& least aqueous solubility Low energy state Highest MP Least aqueous solubility 20

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PREFORMULATION STUDIES b) Metastable polymorphs The remaining polymorphs are called as Metastable forms which represents the highest energy state, low MP, highest aqueous solubility Highest energy state Low MP Higher aqueous solubility In detail: Since the Metastable form have greater aqueous solubility they show better bioavailability and preferred in formulation E x 1 : C hloramphenicol palmitate This exists in 4 polymorphs in that 3 are crystalline (A B & C) & one is amorphous one. A B & C, the B form shows best bioavailability due to metastable form , yielded a higher blood concentration compared to other forms upon oral administration of 1.5gm of dose. 21

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PREFORMULATION STUDIES E x 2 : R iboflavin The polymorphic form III of riboflavin is 20 times more water soluble than the for I. E x 3 : S ulphameter. It exist as 6 polymorphs, crystalline form II is about twice as soluble as crystalline form III . The rate and extent of absorption of sulphameter is 40% greater after administration of II than of III . As Metastable are more soluble in the aqueous so they have greater bioavailability , but only 10% of pharmaceuticals are present in there Metastable forms due to there poor thermodynamic stability . The aging of dosage forms containing Metastable forms usually results in formation of less soluble stable polymorph . 22

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PREFORMULATION STUDIES E x : The more stable crystalline form II of cartisone actate converts to less soluble form V in an aqueous suspension resulting in caking of solid . Inhibition to transformation of Metastable to stable form. ….by dehydrating the molecule environment. …..by adding viscosity building macromolecules such as PVP, CMC, Pectin, Gelatin. gelatin that prevent such a conversion by adsorbing onto the surface of the crystals. 23

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PREFORMULATION STUDIES Crystal properties : Polymorphism Practically all the substance are handled in powdered form at some stage during manufacture in to dosage forms . Crystalline form varies in physical properties dissolution and solid state stability & also process behaviors Polymorphic transition can also occurs during milling, granulating, drying, compression, operations . E.g.: 1) Transition during milling for digoxine & Spironolactone , 2) Granulation can result in solvate formation. 3) Metastable to stable after aging. 24

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PREFORMULATION STUDIES C rystal properties & P olymorphism Crystal characteristics and Bioavailability. B) Crystal characteristics and Chemical Stability. C) Crystal characteristics and Tableting Behavior. D) Crystal characteristics and Physical stability. 25

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PREFORMULATION STUDIES Crystal characteristics and Bioavailability. D ifferent polymorphic forms of a given drug shows difference in the dissolution rate & solubilities .When absorption of drug is dissolution rate limited, as more soluble and faster dissolving form may be utilized to improve the rate and extent of bioavailability. E x …. C hloramphenicol palmitate Comparative blood level data obtained in human after oral administration of 1.5gm of pure A & pure B forms of Chloramphenicol palmitate & their mixtures. These data shows that the pure form B is more soluble so was most bioavailable. Where as pure form A is less soluble so least bioavailable. PURE A -Less soluble -Least bioavailability PURE B -More soluble -Most bioavailability 26

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PREFORMULATION STUDIES B) Crystal characteristics and Chemical Stability. For drugs prone to degradation in the solid state, the physical form of drug influence the rate of degradation . E x…. Aztreonam ( monobactam antibiotic) Exist in needle like α and spherical β -crystalline forms . In the presence of high humidity ( 37 C / 75% RH), the α -form undergoes β -lactum hydrolysis more readily with a half life of about 6 months Where as the β -form under identical condition is stable for several years . In as much as two crystal forms of labile drugs could exhibit widely different solid state stabilities. So the Preformulation scientist might have consider changing the crystal form for eliminate a stability problem. 0 27

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PREFORMULATION STUDIES - - - - - - - - 100 80 60 50 40 30 20 10 0 4 8 12 16 % REMAINING Crystalline solvate Anhydrous crystalline Dissolved crystalline solvate Fig : SOLID STATE DECOMPOSITTION OF DIFF. POLYPHORMIC FORMS OF AN EXPERIMENTAL DRUG Under the stress condition, anhydrous crystalline form of the experimental drug degraded rapidly with a half life of 18 weeks. Solvate form of the drug under some condition was essentially stable . The dissolved form degraded most rapidly . Time (week) 28

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PREFORMULATION STUDIES C) Crystal characteristics and Tableting Behavior . In a typical tableting operation flow and compaction behaviors of the powder mass to be tabled are important. These properties among other are related to morphology, tensile strength, and density, of the powder bed Two polymorphic forms of same drug could differ significantly respect to these properties. The morphology of crystal also depends on crystal habit in which environment changes external shape of a crystal without altering their internal structure . Then a different habit results. Crystal habit is influenced by presence of an impurity , concentration , rate of crystallization , and hydrodynamics in crystallizer . 29

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PREFORMULATION STUDIES D) Crystal characteristics and Physical stability. One form of the polymorphic form is thermodynamically stable at given tempt.& pressure. The other form convert to the stable form that time. This transformation may be rapid or slow. When the transformation is not stable the thermodynamically is unstable form is referred to as meta stable form The stable polymorph exhibit highest melting point, the lowest solubility and maximum physical and chemical stability under safe condition to justify its use for reason of better dissolution or ease of tableting. Whenever Metastable form is remanded a Preformulation scientist must assure its integrity under a variety of processing conditions. Polymorphic transformation can occur during grinding, granulation, drying, and compressing operation. Ex…. Digoxine, Spironolacton, and estradiol are reported to under go, polymorphic transformation during the size reduction. 30

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PREFORMULATION STUDIES Ex… Phenylbutazone under goes polyphormic transformation as a result of grinding and compression. Granulation since it make use of a solvent molecule, can lead to solvate, formation A solvate molecule change to anhydrous crystalline form or amorphic form in drying step. Polymorphic stability is also needed to predict long term physical stability of dosage form. Ex…. Capping like cracking in tablets of anhydrous crystalline carbocromen hydrochloride upon storage under high humidity condition This was determined due to transformation of the anhydrous form into a dehydrate form. 31

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PREFORMULATION STUDIES Various techniques used to determine crystal properties ( Polymorphs) 32

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PREFORMULATION STUDIES TECHNIQUS FOR THE STUDY OF CRYSTAL PROPERTIES 2. Hot stage microscopy 3. Differential Thermal Analysis (DTA) 4. Differential Scanning Colorimetry (DSC) 5. Single crystal X-ray diffraction technique 6. Powder X-ray diffraction technique 7. I.R. Spectroscopy 8. Dilatometry 9. Thermo Gravimetric Analysis (TGA) 1. Microscopy 10. Other methods 33

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PREFORMULATION STUDIES 1. Microscopy Isotropic – only one refractive index E.g. NaCl ( cubic crystalline form) . They do not transmit light, and they appears black . Material with more than one refractive index are anisotropic and appears bright with brilliant colors ( bifringes) against the black polarized background. The interference colures depends on the crystal thickness and the differences in refractive indices Most drugs are either uniaxialy having two refractive indices Most drugs are biaxial corresponding to either an orthorhombic, monoclinic, Or triclinic crystal system. Proper orientation of the crystal along its crystallographic axes is required to describe the crystalline form completely 34

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PREFORMULATION STUDIES A protein crystal seen under a microscope . Crystals used in X-ray crystallography are generally smaller than a millimeter across 35

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PREFORMULATION STUDIES 2.Hot stage microscopy This is visual observation of MP under a microscope equipped with a heated and lagged sample stage. The heating rate is controlled and up to three transition can be registered. It is most precise since the phase transition ( 1 melt , 50% melt, & completion ) can be resister on the recorder as the melting proceeds. And by virtue of high magnification The values are more accurate. st A polarizing microscope fitted with hot stage is useful instrument for investigating polymorphism Sample size required is only 1 mg . 36

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PREFORMULATION STUDIES Hot stage microscope 37

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PREFORMULATION STUDIES 3. Differential Thermal Analysis (DTA) The advantage is that the sample size required is only 2-5mg . DTA measures the tempt difference between sample and reference as a function of temperature or time when heating at constant rate. 38

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PREFORMULATION STUDIES The crystal used in this experiment is lithium fluoride. Assuming that the large flat face will be perpendicular to a particular crystallographic direction, this is set parallel to the line containing the source and detector at θ = 0.  The gearing of the counter arm is such that, once set, the θ - 2θ relationship between the incident, transmitted and diffracted beams is maintained. Using the 2θ value observed at a peak of intensity, the known wavelength λ for Cu Ka, = 1.54Å and the Bragg equation, a value for the plane spacing (d spacing) can be determined. If the peaks can be indexed, i.e. assigned to scattering from certain planes, then from simple geometry lattice parameters can be calculated. This is shown later in the TLP . 39

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PREFORMULATION STUDIES 4. Differential Scanning Colorimetry (DSC) DST is also like to DTA except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference i.e. it measures the enthalpy of transition. When no physical or chemical changes is occurring within the sample then there is neither a temperature change nor the need to input energy to maintain an isotherm However when phase change occurs then latent heat suppresses the tempt increases or fall and the change in tempt required resisters on a recorder as a result of an electrical signal generated by thermocouple. 40

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PREFORMULATION STUDIES Differential Scanning Calorimeter (TA Instruments Q100) 41

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PREFORMULATION STUDIES 42

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PREFORMULATION STUDIES 5. Single crystal X-ray diffraction technique . It provide the most complete information about solid state (identification & description) This method is based on the scattering of x-ray by crystals By this method one can identify the unit cell dimensions & conclusively establish the crystalline lattice system & provide specific differences between crystalline forms of given compound. It is tedious time consuming so it is not used or unsuitable for routine use. 43

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PREFORMULATION STUDIES 44

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PREFORMULATION STUDIES 6. Powder X-ray diffraction technique. Important technique for establishing the batch to batch reproducibility of crystalline form Random orientation of crystal lattice in a powder sample causes x-ray to scatter in a reproducible pattern of peak intensities at distinct angle Ө relative to the incident beam. Each diffraction pattern is characteristics of a specific crystalline lattice for a given compound. An amorphous form dose not produce a pattern . In this mixture of different crystalline forms can be analyzed by using normalized intensities at specific angle which are unique for each crystalline form 45

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PREFORMULATION STUDIES 1 2 3 4 5 20 40 60 100 6 7 80 Intensity ratio % form B Fig: X-ray intencity ratio as a function of composition of form A & B of Chloramphenicol palmitate. 46

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PREFORMULATION STUDIES Electron powder pattern (red) of an Al film with an fcc spiral overlay (green) and a line of intersections (blue) that determines lattice parameter 47

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PREFORMULATION STUDIES 7. I.R. Spectroscopy Different packing arrangement will affect energy of the molecular bond thus altering the I.R. Spectra. Solid samples must be used since polymorphs of a compound have identical spectra in solution . 48

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PREFORMULATION STUDIES Dilatometry measures the change in volume caused by thermal or chemical effects. It has been used to follow the melting behavior of theobroma oil by measuring the specific volume of both rapidly and slowly cooled theobroma oil as a function of increasing tempt . This technique is extremely accurate, however it is extremely tedious and time consuming . It is widely used . 8. Dilatometry 49

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PREFORMULATION STUDIES 9. Thermo Gravimetric Analysis (TGA) is a type of testing that is performed on samples to determine changes in weight in relation to change in temperature . Such analysis relies on a high degree of precision in three measurements: weight, temperature, and temperature change. As many weight loss curves look similar, the weight loss curve may require transformation before results may be interpreted. A derivative weight loss curve can be used to tell the point at which weight loss is most apparent. Again, interpretation is limited without further modifications and deconvolution of the overlapping peaks may be required. 50

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PREFORMULATION STUDIES TGA is commonly employed in research and testing to determine characteristics of materials such as polymers , to determine degradation temperatures, absorbed moisture content of materials, the level of inorganic and organic components in materials, decomposition points of explosives , and solvent residues. It is also often used to estimate the corrosion kinetics in high temperature oxidation . 51

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PREFORMULATION STUDIES 52

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PREFORMULATION STUDIES Other methods such as…. PMR -- Proton Magnetic Resonance, NMR – Nuclear Magnetic Resonance, SEM -- Scanning electron microscopy….. ……..Have additional application for studding polymorphism. 53

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PREFORMULATION STUDIES Thermal analysis methods are easy to use techniques for material characterization and optimization. These methods can provide crucial information regarding the behavior of a material or part at elevated temperatures. Thermal analysis is a more and more important part of each analytical laboratory in industrial and university research. Introduction to thermal methods 54

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PREFORMULATION STUDIES Contemporary DSC instruments are characterized not only by high sensitivity but by the high stability of their baseline and the ability to scan aqueous solutions up to and above 100 °C under excess pressure and by super cooling down below 0 °C. The wide operational range is important because changes of many macromolecules take place over a very broad temperature range. As for the stability of the baseline, this is important since it permits determination of the partial heat capacity of the solute (macromolecule) in dilute solution. As shown below, knowledge of the absolute partial heat capacity of macromolecule over a wide temperature range opens new prospects for studying their thermodynamic properties [2] . According to different measurements, DSC can be distinguished as Power Compensation DSC and Heat Flow DSC. 55

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PREFORMULATION STUDIES 56

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PREFORMULATION STUDIES tg 57

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PREFORMULATION STUDIES 58

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PREFORMULATION STUDIES 59

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PREFORMULATION STUDIES Solvates / Hydrates. (Psudopolymorphism) 60

PHYSICAL DEGRADATION OF PHARMACEUTICAL PRODUCTS:

PHYSICAL DEGRADATION OF PHARMACEUTICAL PRODUCTS Loss of Volatile Constituents Ex :- Iodine, Camphor, Menthol, Nitroglycerine tablets. Loss of Water Ex :- Borax, Caffeine, Emulsions exhibit cracking. Absorption of Water Ex :- Gelatin capsules, calcium chloride. Colour Changes Ex :- Aspirin tablets – Pink Ascorbic tablets – Yellowish brown 61 PREFORMULATION STUDIES

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PREFORMULATION STUDIES Drug degradation can occurs by… Temperature Hydrolysis Oxidation Photolysis Presence of metal ions pH Hygroscopisity Solvolysis 62 The drug product must be stable chemically, physically, toxicologically, and therapeutically.

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PREFORMULATION STUDIES Temperature ACCELARATED DEGRADATION OF A DRUG IN SOLUTION AT ELEVETED TEMPRETATURE ARRHENIUS PLOT OF PREDICTING THE RATE CONSTANT AT AMBIANT TEMPRETURE 63

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PREFORMULATION STUDIES The general procedure involves …. Storing the product/drug samples at different temperatures They are withdrawn at different time period intervals & observe for physical, chemical, microbiological changes , level of impurities ,degradation products. If significant changes are observed at the accelerated condition . It is advisable to analyze the same sample at normal temperatures conditions In case degradation product are observed change the packaging material 64

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PREFORMULATION STUDIES 2. Hydrolysis Most likely cause of drug instability is hydrolysis . Water plays a dominant role & in many cases it is implicated passively as a solvent vector between two reacting species in solution 65

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PREFORMULATION STUDIES Hydrolytic reaction involves nucleophilic attack of labile bonds Ex… lactum > ester > amide > imides . by water on the drug in solution. When the attack is by the solvent other than water is called as ‘ Solvolysis’ A no. of condition catalyses the break down The presence of OH group The presence of H 3 O The presence of divalent metal ions Ionic hydrolysis Heat Light Solution polarity & ionic straingth High drug concentration 66

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PREFORMULATION STUDIES Prevention of Hydrolysis By passing an insoluble salt form By preparing solid dosage form By replacement of water by some other solven ts. Ex.: such as Alcohols or Polyhydroxy solvents Example1. Aspirin suspensions showed improved stability on addition of high concentration of sorbitol Example2. Ampicilline also showed good stability on addition of alcohol . 67

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PREFORMULATION STUDIES 3.Oxidation All oxidative products are toxic Heavy metal such as cupric ions or ferric ions accelerate the oxidation of ascorbic acid and phenothiazines 68

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PREFORMULATION STUDIES During storage of formulation undergo oxidation by atmospheric oxygen. Sometimes oxidation can be occurs due to the secretion of enzymes produced by microorganism so in this case problem is avoided by adding a suitable antimicrobial preservative. Studies should be initiate to establish the oxidative route and steps taken to determine what additives can be added to formulation to minimize the degradation Oxidative degradation is common with drugs as …. Ascorbic acid Epinephrine Vitamin A Chlorpromazine Morphine Unsaturated oils and fats. 69

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PREFORMULATION STUDIES Some times pH is critical, since a greater number of oxidation-reduction processes depends on the concentration of hydrogen and hydroxyl ions. Light usually accelerate degradation , thus storage of products in ambered colored container can prevent this problem. Auto oxidation can occurs when material such as fats and oils are stored in the presence of air . Ex.. Phenolic compounds like Epinephrine and Isoproterenol 70

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PREFORMULATION STUDIES Prevention of oxidation The oxygen concentration in solution is a factor in many cases and often depends on the temperature of storage or solvent employed . Oxygen is more soluble in water at lower temp Ascorbic acid is more stable in 90% propylene glycol or in syrup than in water because of lower oxygen concentration in the vehicle. Preparation sensitive to oxidation are some times stabilized by effectively removing the oxygen and by addition of suitable antioxidants 71

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PREFORMULATION STUDIES Antioxidants Ascorbic acid Sodium bisulfite Sodium metabisulfite Butylated hydroxy toulene Butylated hydroxy anisole Tocopherols Citric acid and Chelating agent 72

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PREFORMULATION STUDIES 4. Photolysis Oxidation and to some extent Hydrolysis is often catalyzed by light. The energy associated with the reaction increases, as the wave length decreases, so that the energy of UV visible is greater than that of IR. And it is independent of temperature. When molecule are exposed to E M Radiation they absorb light at characteristics wavelengths which cause an increase in energy, which can …. cause decomposition be retained or transferred be converted to heat result in emission of light at a new wavelength( Fluorescence & Phosphorescence) 73

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PREFORMULATION STUDIES Natural sunlight lies in the wave length range 290-790nm of which only the energy UV range 190-320nm causes photo degradation of drug and sunburn Prevention of photolysis : Use Packaging material like : Ex …. Low actinic amber glass bottles Card board outers Aluminum foil Over wrappers and blisters Plastic containers 74

5) Presence of metal ions :

5) Presence of metal ions PREFORMULATION STUDIES Chelating agents are complexes , unlike simple ligands Ex... Ferrocinide which forms complex salts by a single bond provided by a lone electron pair Chelating agents are capable for forming more than one bond Ex… Ethylene Diamine Tripyridine EDTA 75

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PREFORMULATION STUDIES 6) p H The degradation of most drug is catalyzed by the extreme of ph i.e. high [ H 3 O ] and[ OH ] many drugs are most stable between pH 4 to 8. Injections should have low buffer capacity to prevent un necessary challenges to the homeostatic pH of the blood The increase of water miscible solvents in the formulation will be increase stability by Suppressing ionization reducing the extreme of pH required to achieve solubility. Reducing water activity by reducing the polarity of the solvent Ex….. 20% propylene glycol in Chlordiazepoxide injection 76

7) Hygroscopicity :

7) Hygroscopicity PREFORMULATION STUDIES A substance which absorb sufficient moisture from the atmosphere is called hygroscopic -- Deliquescent -- Efflorescent . Most pharmaceutical compounds lose or gain water from the atmosphere depending on the relative humidity (RH) Materials unaffected by RH is termed as non hygroscopic 77

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PREFORMULATION STUDIES Why do we care about Hygroscopicity Amorphous compounds may take up water and re-crystallize and or degrade Anhydrous material may hydrate and become less soluble The weight change with sorption may cause errors in potency The volume changes associated with water gain and loss may compromise dosage form integrity Changing the solid state form in the dosage form requires regulatory approval Different forms may have different compaction, flow and charging characteristics 78

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PREFORMULATION STUDIES 79 Prevention of Hygroscopicity Good packaging ( air tight) Use of foil blisters Use of desiccants.

8) Solvolysis :

8) Solvolysis PREFORMULATION STUDIES Where the reacting solvent is not water then break down is termed as solvolysis. or Any change in solvent polarity ( usually measures as dielectric constant ) as result of increase ionic strength . If the compound produce degradation product which are polar than itself then the addition of less polar solvent will stabilize the formulation and vice versa . With the hydrolysis of neutral non polar drugs such as steroids the transition state will be non polar and with no net charge In this case solvent will not affect the rate of decomposition and can be used to increase stability. 80

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PREFORMULATION STUDIES Solution stability These studies include the effect of pH , Ionic strength, Co solvent, Light , Temperature, and Oxygen 81

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PREFORMULATION STUDIES Solid stability “The primary objective of this study is investigation and identification of stable storage condition for drug in the solid state and identification of compatible excipients for a formulation.” In all solid dosage formulation there will be some free moisture ( contributed by excipient as well as the drug ) And certainly in tablets a significant percentage typically 2% w/w is required to facillate good compression. This free water has ability to act as a vector for chemical reaction between drug and excipients and the absorbed moisture films are saturated with drug compared to the dilute solutions encountered in injectables. 82

STABILITY TESTING OF PHARMACEUTICAL PRODUCTS:

PREFORMULATION STUDIES STABILITY TESTING OF PHARMACEUTICAL PRODUCTS It is first quantitative assessment of chemical stability of new drug Defined as “ The capability of a particular formulation in a specific container/ closer system, to remain within its physical chemical ,microbiological, therapeutic, and toxicological specifications throughout its self life ” 83

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PREFORMULATION STUDIES Stability is officially defined as “the time lapse during which the drug product retains the same properties & characters that is processed at the time of manufacture”. The stability of a product is expressed as the expiry period or technically shelf life . 84 shelf life the time from the date of manufacturing & packaging of the formulation until its chemical or biological activity is not less than a predetermined level or labeled potency & its physical characteristics have Not changed appreciably or deleteriously Expiry date is the time in which the preparation will remain stable when stored under recommended condition

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PREFORMULATION STUDIES 85 Stability studies are important for the following reasons 1. Assurance to the patient 2. Legal Requirement 3. Economic Repercussions.

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PREFORMULATION STUDIES 86 TYPES OF STABILITY CONDITIONS MAINTED DURING THE SHELF LIFE OF THE PRODUCT Chemical Retains its chemical integrity & labeled potency Physical Appearance; palatability; uniformity; dissolution, and suspendability are to be retained Microbiological Retains sterility; effectiveness of antimicrobial agents Therapeutic Drug action remains unchanged Toxicological No significant increase in toxicity

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PREFORMULATION STUDIES Purpose of stability study To ensure the efficacy of drug substance dosage form. To ensure the safety of drug substance dosage form. 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 excipients and other additives. To determine the dosage form in which the drug is most suitable. 87

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PREFORMULATION STUDIES Factors affecting stability Storage time Storage condition Type of dosage form Container and closer system 88

Useful guide lines:

Useful guide lines PREFORMULATION STUDIES Many useful guidelines are available to address most of the stability- associated problems. These guidelines includes ……. - ICH ( International Conference for Harmonization) - CPMP ( Committee for Proprietary Medicinal Product) - FDA ( Food and Drug Administration ) & - WHO ( World Health Organization ) 89 Recent year the pharmaceutical dosage forms are becoming more & more complex & diverse. Due to.. many novel dosage forms New drug targeting systems. Have been introduced. In addition finding a right approach for estimation self life has becomes challenging…..

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PREFORMULATION STUDIES Generation of stability data The first step in stability data generation is the documentation of detailed stability protocol. The protocol depends upon type of drug Type of dosage form proposed container closer system and the target market area its average temperature . & percentage Container and closer Container orientation during test period Sampling intervals Type size and number of batches Plan of sampling Storage condition Test parameters. Test methodology, Acceptance criteria. 90

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PREFORMULATION STUDIES 91 Container and closures b) Container orientation during test period Testing should be done using the containers and closures proposed for storage and distribution. For physician sample, Promotion & marketing sample Bulk storage sample The protocol should provide information about type, size, and source of containers & closures system. …important for solutions , dispersion systems and semisolid products Because the interaction between dosage form and container-closure system is more in these cases. For storage any one of the following three deferent positions can be selected Upright position can be use to study the effect of temperature & relative humidity on the dosage form where as Inverted and on the side position can be used to study the interaction between product-container-closure & also to find out adsorption of product component by container-closure system.

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PREFORMULATION STUDIES 92 c) Sampling intervals Different guidelines suggest different sampling intervals for real time stability testing, intermediate testing & accelerated stability testing. According to ICH Q1A & CPMP-QWP/556/96 Relative humidity.

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PREFORMULATION STUDIES 93 GUIDELINES APPLICABILITY MINIMUM NO.OF BATCHES SIZE AND TYPE ICH Q1A WHO NEW DRUG SUBSTANCES NEW DRUG PRODUCT PRODUCT CONTAINING EASILY DEGRADABLE ACTIVES PRODUCT CONTAINING ESTABLISHED & STABLE SUBSTANCES 3 3 3 3 PIOLET SCALE TWO PILOT SCALE, ONE SMALL SCALE PIOT OR FULL SCALE PRODUCTION DIFEERENT PRODUCTION BATCHES d) Type, size and number of batches to be tested for stability assessment

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PREFORMULATION STUDIES 94 Guidelines for real time testing During first year sampling should be done every three months . During second year sampling should be done for every six months and after two years sampling should be done once in a year. Accelerated testing should be done for at least six months according to ICH-QIAR(Oct 99) and it suggest sampling point of 0,3 and 6 months for stable product. The FDA guidelines suggest sampling intervals of 0, 2, 4 and 6 months . WHO guideline suggest 0, 1, 2, 3, and 6 months sampling intervals.

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PREFORMULATION STUDIES 95 e) Plan of sampling In this the total no. of containers & closures for stability test should be determined . At least two containers are to be sampled during the stability study . After determination of total no of samples , a sampling plan should be made so that the selection of samples is not arbitrary and the selected containers should represent the batch as whole FDA suggest a method in which from a random sampling point, every n th container is selected from filling or packaging line and ‘n’ is chosen such that the sample spreads over whole batch

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PREFORMULATION STUDIES Serial no. zone Mean kinetic temp( MKT) Yearly average humidity ( %RH) 1 Zone-I ( moderate ) 21 C 45 2 Zone-II ( Mediterranean ) 25 C 60 3 Zone-III ( Hot, Dry) 30 C 35 4 Zone-IV (very Hot, Moist) 30 C 70 O o o o World wide zones and temperature and humidity conditions 96 f) Storage condition For accelerated stability testing the samples are stored under isothermal condition and for long term stability testing ( real time testing ) the containers are stored in open selves in ventilated areas. HAYNES divide the countries of world into four zones .

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PREFORMULATION STUDIES Zone I and II Zone III and IV Europe ( all countries) , Argentina . Chile . Canada . Mexico, Peru. US . Brazil. Guyana. Colombia. Cuba. Dutch. Panama. Paraguay. Afghanistan. China . Iran . Japan . Nepal . Korea . Turkey . Egypt . Libya . Namibia . South Africa . Zimbabwe. Australia . New Zealand . Bangladesh. Hongkong. India. Iraq. Pakistan. Jordon. Myanmar. Oman. Singapore,. Sreelanka. Taiwan. Saudi. Gambia. Ghana. Kenya. Madagascar. Uganda. Ethiopia. Fiji. Tonga. Countries belonging to various stability zone 97

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PREFORMULATION STUDIES 98 PRUDUCT ACCELRATED TYPE OF STUDY INTERMEDIATE LONG TERM Solid oral dosage form, for reconstitution. Dry & lyophilized powder in glass vials Liquid in glass bottles, vials, scaled glass ampules , which provide an impermeable barrier to water loss. Drug products in semi permeable containers Drug product intended to be stored at refrigerator temperature Drug products intended to be stored at freezer temperature 40 C/75%RH C/ ambient humidity 40 C/15%RH 25 C/60% RH or 25 C /ambient humidity for liquid products 5 + 3 C/ ambient humidity C /60% RH 30 C / ambient humidity 30 C/40%RH C /69% RH 25 C/ambient humidity C/40%RH 5+3 C with monitoring but not control of humidity - 15+ 5 C Storage condition for zone I & zone II countries

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PREFORMULATION STUDIES 99 PRUDUCT Types of ACCELRATED Study LONG TERM Solid oral dosage form, for reconstitution. Dry & lyophilized powder in glass vials Liquid in glass bottles, vials, scaled glass ampules , which provide an impermeable barrier to water loss. Drug products in semi permeable containers Drug product intended to be stored at refrigerator temperature Drug products intended to be stored at freezer temperature 40 C/75%RH C/ ambient humidity 40 C/15%RH 25 C & 35 C/75% RH or 30 C /ambient humidity for liquid products 5 + 3 C/ ambient humidity 30 C & 35 C/70% RH 30 C/ambient humidity 30 C/40%RH 5+3 C with monitoring but not control of humidity -15+ 5 C Storage condition for zone III & zone IV countries

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PREFORMULATION STUDIES 100 g) Test parameters Physical parameters to be evaluated for different dosage form Dosage form Physical parameters Solutions Change of color Change of odor Clarity Appearance( precipitate, cloudiness) pH Dosage form Physical parameters 2. Suspensions Appearance ( precipitate, cloudiness) pH Color , odor Redispersibility Dosage form Physical parameters 3. Tablets Appearance Friability Hardness Color , odur Dissolution Moisture absorption

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PREFORMULATION STUDIES 101 Dosage form Physical parameters 4. Hard gelatin capsule Moisture Color brittleness Appearance( shape) pH Dissolution Dosage form Physical parameters 5. Soft gelatin capsule Moisture Color Brittleness Appearance( shape) pH Dissolution Precipitate Cloudiness Dosage form Physical parameters 6. Emultions Moisture Color , odor. Cloudiness Appearance( phase saperation ) pH Precepitate

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PREFORMULATION STUDIES 102 Dosage form Physical parameters 7. Creams & ointments Moisture Color & odor brittleness Appearance & clarity Homogenicity pH Resuspendibility ( for lotions) Consistency (viscosity) Weight loss (plastic containers) Particle size

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PREFORMULATION STUDIES 103 h) Test methodology For all the parameters included in the protocol , suitable method should be established and standard test procedure should be prepared For the assay of drug all the guidelines suggest the establishment of sensitive stability indicating method The method should be validated for specificity accuracy precision and linearity along with assay of drug should also be done for degradation product

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PREFORMULATION STUDIES 104 i ) Acceptance criteria The criteria for quantitative result will be in terms of numerical limits Ex….. moisture , absorbance drug assay in terms of % For qualitative tests the criteria may be in term of pass or fail Ex….. color change odor change degradative changes For each test include in the protocol a suitable acceptance criterion should be fixed

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PREFORMULATION STUDIES 105 Conducting stability study & recording the data Once the protocol is ready the stability study should be conducted by keeping the dosage form is final container under selected storage condition Sample should be withdrawn at the predetermined sampling intervals and the analysis of drug in dosage form should be done The sample should be withdrawn from unopened container and after the withdrawn the processing of sample should be done immediately Assay for drug , assay for impurities and degradation products should also be done. Stability data collected must be recorded in an organized format. lik e….

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Signature : Sample format for stability data recording Sr.no Sample withdrawal day Date of analysis % potency retained ( Mean + SD) 5 C 25 C/ 30 C/ 40 C/ 50 C fluore - xenon U V 60% 60% 75% ambient scent light light RH RH RH humidity 1 0 th day (initial) 2 30 th day (1month) 3 60 th day(2 month) 4 90 th day(3 months) 5 180 th day(6 months) o o o o o Name of the product/ strength: Batch no. Batch size. Container/size/supplier: Date of packaging: Study number: Mfg date: Mfg site: Closure composition supplier: Storage orientation: Date of starting the study:

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Signature: Degradation product Initial 1 month 2 months 3 months 6 months 9 months 12 months 18 months 24 months 36 months Degradation product “A” Degradation product “B” Degradation product “C” Degradation product “D” Degradation product “E” Percentage observed Name of the product/ strength: Batch no. Batch size. Container/size/supplier: Date of packaging: Study number: Mfg date: Mfg site: Closure composition supplier: Storage orientation: Date of starting the study: Sample format for recording of impurity & degradation product data

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PREFORMULATION STUDIES 108 Estimation of self life After recording the data , the final step is the estimation of self life or expiry date. The guidelines suggest an approach, which is different from the conventional approach of stability testing Conventionally multi- temperature accelerated studies Arrhenius approach ……were used for estimation of self life , but there are several drawbacks in Arrhenius approach .. It applicable only for cases where drug degradation is reasonable and rate or order of reaction can be determined. In this approach , linear regression is applied even though the data is not linear. Errors associated with determination of drug content are not included. Above critical temp degradation mechanism may change and in this case also Arrhenius approach becomes invalid

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PREFORMULATION STUDIES 109 So due to the drawbacks in in Arrhenius approach the ICH, CPMP and FDA guideline suggest ‘ self life determination should be based on real time testing data through application of appropriate statistical technique ’

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PREFORMULATION STUDIES 110 It is necessary that the stability testing all over world be oriented to words uniformity, which can be achieved by using international guidelines . this is important because of world trade agreement and GATT ( general agreement on tariff and trade). This will provides the manufacturers to go for international marketing……

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K = Se /RT -Ha Where: k = specific rate of degradation R = gas constant (1.987 calories degree mole ) T = absolute temperature S = frequency factor Ha= The heat of activation By integrating the Arrhenius equation…. Converting to log 10 : - 1 - 1 In k = - + In S ∆Ha RT A B Log k = - . + log S ∆Ha 2.303 R 1 T C

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112 From equation ( C) a plot of log k verses 1/T yields a slope equal to - from which the value for the heat of activation can be calculated. The heat of activation ( ∆Ha ) represents the energy the reacting molecule must acquire to undergo reaction ∆Ha 2.303 R Temperature dependency of degradation rate

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PREFORMULATION STUDIES 113 Values of t 10% at several temperatures

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PREFORMULATION STUDIES 114 So due to the drawbacks in in Arrhenius approach the ICH,CPMP and FDA guideline suggest ‘ self life determination should be based on real time testing data through application of appropriate statistical technique ’

PHYSICO-CHEMICAL CHARECTERSTICS OF NEW DRUG MOLECULE:

PREFORMULATION STUDIES PHYSICO-CHEMICAL CHARECTERSTICS OF NEW DRUG MOLECULE Solid dosage form Semisolid dosage form Parenterel / sterile dosage form Liquid dosage form… With respect to …Dosage forms 115

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PREFORMULATION STUDIES PHYSICO-CHEMICAL CHARECTERSTICS Of Tablets Synonym of the compound Chemical structure Molecular weight Chemical name Therapeutic category Description (appearance) Taste Odour Source (natural drugs) Solubility Melting point Assay Identification tests 14. Specific rotation 15. pH 16. Loss on drying 17. Residue on ignition 18. Presence of heavy metals 19. Powder properties 20. Moisture content 21. Determination of lambda max 22. Standard calibration curve 23. Compatibility studies 116

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PREFORMULATION STUDIES PHYSICO-CHEMICAL CHARECTERSTICS Of PARENTERAL DOSAGE FORMS Synonym of the compound Chemical structure Molecular weight Chemical name Therapeutic category Description (appearance) Taste Odour Source (natural drugs) Solubility Melting point Assay Identification tests 16. Loss on drying 17. Water content 18. Presence of heavy metals 19. Powder properties 20. Microbiological count 21. Determination of lambda max 22. Standard calibration curve 23. Compatibility studies 24. Screening of glass used for packaging 25. Determination of viscosity 14. Specific rotation 15. pH 117

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PREFORMULATION STUDIES PHYSICO-CHEMICAL CHARECTERSTICS Of Liquid dosage form Synonym of compound Chemical structure Molecular weight Chemical name Therapeutic category Description Taste Odor Solubility Assay Melting point Identification test Specific rotation pH Accelerated studies Viscosity of excipients 118

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PREFORMULATION STUDIES PHYSICO-CHEMICAL CHARECTERSTICS Of Semisolid dosage form Appearance Clarity Color Odor Homogeneity Irritancy Miscibility with skin secretion and serum Compatibility with skin secretion emollient properties pH Consistency( viscosity) Resuspendibility Weight loss Particle size 119

References ::

PREFORMULATION STUDIES References : The theory and practice of industrial pharmacy by Leon Lachman page no.176. Ansel’s Pharmaceutical dosage form and drug delivery system. by Ansel . page no.92. ‘Pharmaceutics’ –The science of dosage form formulation by Aulton . Page no.223. ‘ Biopharmaceutics and Pharmacokinetics’ by Brahmankar page no 27. ‘Instrumental methods of chemical analysis’ by Chatwal and Anand . ‘ Biopharmaceutics and Pharmacokinetics’ by Shobha rani . ‘Modern Pharmaceutics’ IIIrd edition by Gilbert S. Banker. ‘Controlled drug delivery’ by Robinson ‘Internet sources’ Article by G.T. Kulkarni & B. Suresh,in Indian J.PharmEduc.38(4)oct-2004. 120

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PREFORMULATION STUDIES Thank you ! thaNK you !!! 121

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