Stability Studies:: Pharmaceutical Product Development

STABILITY STUDIES:
PHARMACEUTICAL PRODUCT DEVELOPMENT
GUNDA NAREH Khammam College O f Pharmacy 09000060616
ROADMAP
Introduction Overview of stability studies Zone concept Stability of drug substances (physical, chemical and microbiological) Stability of specialized products Stability protocol Stability data handling Regulatory requirements Conclusion
INTRODUCTION
Pharmaceutical product development involves in development of safe, efficacies and quality product Pharmaceutical analysis and stability studies play a key role in successful product development Stability studies involved in determination and assurance of identification, potency and integrality of active substances as well as formulation
INTRODUCTION
Stability of products is defined as the extent of period retains its initial properties and characteristics within the specified limit Specific limits to be retained duting storage and usage Product characteristics and properties at the time of packaging to be maintained through put the shelf life
INTRODUCTION
Product properties and characteristics are Physical properties Chemical properties Microbial load Therapeutic properties Toxic characteristics All the above mentioned properties to be maintained with in the specification throughout the shelf life
INTRODUCTION
Stability studies provide evidence of impact of temperature, humidity and light on quality of products Purpose of stability studies Shelf life determination Assigning proper storage conditions Suitable packaging development
INTRODUCTION
Focus of stability testing Chemical (integrity, potency and degradation) Physical (solubility, hardness, sedimentation etc) Microbiological (resistance for microbial growth) Analytical methodologies Chromatography (LC, GC, TLC, LCMS) Thermal analysis (DSC, TGA, DTA) Particle size (CC, PCS, LD)
INTRODUCTION
OBJECTIVE OF STABILITY STUDIES
OBJECTIVE
Select the formulation and packaging
USE
Development of the product
TYPE
Accelerated
Shelf life determination Development of the product and Accelerated and and storage condition preparation of registration real time assessment dossier
Claiming shelf life SUPAC Registration of dossier QA and QC Real time Accelerated and real time
NATURE AND TYPE OF DOSAGE FORM

Product type and its packaging material has influence on drug product stability Hence stability condition should be based on product type and its packaging material Impermeable containers (for example glass containers, humidity is not a parameter): humidity is not an important parameter Whereas humidity is very important for semi permeable containers Semi permeable containers should be stored at low humidity ( example at 25% RH, 35% RH and 40% RH)
NATURE AND TYPE OF DOSAGE FORM

Low humidity conditions used to predict the water loss and associated product instability Products to be stored at refrigeration and deep freezing, proper storage condition should be selected i.e 2-8 oC and -20oC for refrigeration and deep freezing, respectively as a ambient conditions Photo stability to be performed for light sensitive drug with proper containers (amber color) UV energy used for photo stability should not be less than 200 watt hours/ square meter
STABILITY PROTOCOL
Properly well designed protocol is the prerequisite for stability studies Stability protocol should be designed for both formulation development as well as registration batches Key elements should be constant in both the protocols Whereas the extent of stability studies should be lengthy incase of registration batches
STABILITY PROTOCOL
Content of stability protocol Type, size and number of batches Type, size and source of containers and closures Container storage orientation Test time points Sampling plan Plan for storage conditions Test parameters Test methods Acceptable criteria
STABILITY PROTOCOL: BATCHES

For formulation development, single batches stability studies New products and unstable products, three consecutive batches for registration Foe well established products, two batches for registration In case of pilot scale batches, release specification should be similar that of commercial batches Two different batches of API should be subjected for stability to explore the impact of API on stability of drug product
STABILITY PROTOCOL: BATCHES

If initial data is not on full scale batch First three production batch to be subjected for long term stability studies Same protocol of approved drug product should be used in post approval batches Selection of batches should be based on randomization
STABILITY PROTOCOL: CONTAINERS

Containers and closures of formulation and development batch and registration batch should be same that of proposed marketing Secondary packing material should be similar, but not shipment packages For bulk containers, prototype container may be used but should be simulated with actual containers Prequalified containers, closures, labels, adhesives, ink and color should be used during stability studies
STABILITY PROTOCOL: OREINTATION OF CONTAINERS

For solutions, suspensions, semisolid dosage forms and powders, container should be in up right position To ensure the maximum contact with the product to understand the drug-packaging material compatibility Inverted position and onside position is also allowed if the contact between container and product is optimal
STABILITY PROTOCOL: SAMPLING POINT

For formulation development batches, accelerated and stress state stability studies with close sampling points such as 15 days, 1, 2 and 3 month This will help to identify the potential stability changes in minimum period and rapid product development For registration batches, long term and accelerated studies with actual period Long term stability studies should be carried out for full expiry period of the product
STABILITY PROTOCOL: SAMPLING POINT

Bracketing and matrix statistical design is used for sample point selection Bracketing design In case of multiple strength, lowest and highest strength sampling should be carried out in all time pints No need for intermediate strength sampling Matrix design One half reduction in all the strength Sampling point should meet regulatory requirements as well as provide the entire length of information of stability studies
STABILITY PROTOCOL: SAMPLING PLAN

Total number of samples based on the sampling point Test required and the quantity of samples required for each test Selected samples should be represent the quality of entire batch Randomization technique should be adopted for sample selection
STABILITY PROTOCOL: STORAGE CONDITIONS

Storage conditions are based on the product For example ointments and semisolid preparations should be stored at lower temperature (instead of 40oC, it should be 30oC) Generally, accelerated temperature is 15oC more than actual conditions While selecting storage condition, one should consider zone of the proposed marketing country
STABILITY PROTOCOL: TESTING PARAMETER

General testing parameters are Organoleptic properties such as colour, odour, taste incase of liquid and solid oral dosage forms, clarity incase of parenteral solution, re-dispersibility in case of suspension Assay, RS, preservative content, viscosity etc Dissolution, disintegration, hardness incase of tablet dosage forms
STABILITY PROTOCOL: TESTING METHODOLOGIES

Always better to follow the official methodologies Assay method should be carried out using stability indicating assay method Methods should be fully validated for its accuracy, precision and linearity If method is already reported in literature, system suitability and partial validations are mandatory
STABILITY PROTOCOL: ACCEPTANCE CRITERIA

Acceptance criteria should be numerical value It should be quantitative specifications such % moisture uptake, viscosity, particle size and so on Qualitative tests are also acceptable in some case such as color, odor, appearance, cracking, microbial growth etc Limit of acceptance criteria should be set based on the stability available stability data
THERMAL CYCLING
1. 2. 3. 4. Thermal cycling is carried out establish the influence of temperature variation during distribution Thermal cycling is advisable for the products, which has Phase separation Loss of viscosity Precipitation Aggregation Drug products under go temperature variation below sub freezing (-10 to -20C, followed by 40C, two days, three cycles, for twelve days) Drug products under go temperature variation above freezing (2-8C, followed by 40C, two days, three cycles, for twelve days)
CAUSE OF INSTABILITY
Physical stability of drug substances Chemical stability of drug substances Microbial stability of dosage forms Stability of dosage forms in general
PHYSICAL STABILITY
Most studies focused on chemical stability of drug products However, physical stability of the formulation is also equally important for safety, efficacy and quality of drug products In general DSC and PXRD is widely useful techniques to assess the physical stability Physical changes in crystalline form of API in dosage form affect the drug dissolution and drug release subsequently, bioavailability and therapeutic efficacy In Parenterals, crystallization may cause serious problems
PHYSICAL STABILITY
In case of pharmaceutical suspension, sedimentation may be the problem which affect the content uniformity and hence safety and efficacy Moisture up take and hardening and softening of tablets and capsules results with potential bioavailability problem due altered dissolution Incase of solid oral dosage forms, moisture uptake potentiate the hydrolysis of active ingredients and hence alter the chemical stability There are different kind of physical de-formality that could directly affect the quality, safety and efficacy of the drug products.
PHYSICAL STABILITY
Causes of physical degradation Crystallization of amorphous form Transition of crystalline state Formation and growth of crystals Vapor phase transfer including sublimation Moisture adsorption and uptake
PHYSICAL STABILITY
Crystallization of amorphous form Amorphous forms are used to enhance the solubility, dissolution and bioavailability of dosage forms Crystalline substances having low surface free energy and hence thermodynamically stable Amorphous forms possess high free energy and hence thermodynamically unstable Therefore crystallization occurs during storage
PHYSICAL STABILITY
Crystallization of amorphous form
Example is Nifedipine amorphous form are partially crystalized during storage at high RH and resulted with lower in dissolution during storage period
PHYSICAL STABILITY
Another classical example is oxyphenbutazone, relative humidity at variuos level leads different crystals
PHYSICAL STABILITY
Non ionic and cellulosic polymers have been used to reduce the crystallinity This is due polymer matrix reduce the mobility of molecules and prevent the crystal seed formation in both solid as well as liquid state (e.g Haloperidol with different cellulosic polymers)
PHYSICAL STABILITY
Preparation of amorphous formulations have profound effect on stability Spray drying at higher temperature will provide amorphous forms with higher stability High stability of amorphous form is identified with high glass transition temperature Crystallization of amorphous excipients for example sucrose at higher humidity
PHYSICAL STABILITY
CRYSTALLINE STATE TRANSITION

Classical example for polymorphic transition of cianidanol
PHYSICAL STABILITY
CRYSTAL GROWTH
Definition High array of molecules in lattice is called as crystals
Insulin crystals
PHYSICAL STABILITY
CRYSTAL GROWTH
Crystals are even though considered as thermodynamically stable Crystals should not be considered as static one Crystals may grow or reduce in their size depends on the free energy and environment Sublimation of growth of crystals may occur in liquid or gas matrix Crystal growth or sublimation in tablet surface may results whiskering effect Crystallization is favored in high porous tablet matrix at high temperature
PHYSICAL STABILITY
CRYSTAL GROWTH
The extent formation of whisker at 30 C for caffeine and ethezamide
PHYSICAL STABILITY
CRYSTAL GROWTH
Carbamazepine tablets are another classical example for crystal growth Carbamazepine tablets stored at high RH, results with formation of CBZ dihydrate crystals CBZ tablets containing stearic acid, if stored at higher temperature, forms columnar crystals The suggested reason is that stearic acid melt at higher temperature, CBZ gets dissolved in melted steraic acid and recrystallized in different form
PHYSICAL STABILITY
VAPOR PHASE TRANSFER

Sublimation may results with drug molecules contain low melting point Sublimation is the process of phase transfer of solid to liquid with the aid of thermal energy Volatile liquid substances escape form dosage form during storage period and results in poor content uniformity and assay Addition of water soluble, non volatile fixing agent prevent the vapor phase transfer
PHYSICAL STABILITY
VAPOR PHASE TRANSFER

Example content uniformity of nitroglycerin stored at 21 C for 5 months
PHYSICAL STABILITY
MOISTURE ADSORPTION
Moisture adsorption is generally observed with solid pharmaceutical substances Hydrophilic substances adsorbs more moisture Moisture adsorption reduces the chemical stability of drug substances Drug substance prone to hydrolysis are worst affected with moisture adsorption Moisture adsorption affects the pharmaceutical properties such as dissolution, disintegration and hardness Hydrophilic excipients accelerates the rate and extent of moisture adsorption Moisture adsorption is based on RH of the environment
PHYSICAL STABILITY
MOISTURE ADSORPTION
PHYSICAL STABILITY
EFFECT OF WATER ON SOLIDS

Physical stability of solid dosage forms affected by plasticizing effect of water Water increase the molecular mobility and provides the energy And hence increase the rate of crystallization Water decreases the glass transition temperature of amorphous solid substances There are free volumes in amorphous state Water occupied these free volumes and hence act as a medium for mobility of molecules that reduce the enrgy requirement Hence causes low glass transition temperature
PHYSICAL STABILITY
KINETICS OF SOLID PHASE TRANSITIONS

Unlike chemical degradation, detail mechanism of physical degradation process have not been extensively studied However, prediction of some physical degradation associated with polymorphic changes Hancock sharp equation often used to describe the kinetics of polymorphic changes
PHYSICAL STABILITY

Different mechanisms of polymorphic transitions
PHYSICAL STABILITY

Polymorphic transition of carbamazepine It is an temperature dependent phenomenon Possible mechanism is two dimensional nuclei growth The best fit model is Avrami Erofe eq.
STABILITY OF DOSAGE FORMS

Pharmaceutical dosage forms are complex systems Consists of not only active ingredients but also inactive ingredients Dosage forms under go various degradations such as physical, chemical and microbial Stability of dosage form should be controlled in various stages such as selection of drug and excipients as well as dosage form it self Stability of the formulation should be assured in each and every step of formulation development process such as preformulation, selection of excipients, selection of packaging material and so on

Various critical steps and parameters include the formulation stability are Preformulation and formulation development Functional changes in dosage forms with time Effect of packaging on stability of drug products Estimation of shelf life
PREFORMULATION
Preformulation studies are designed To deliver the physicochemical data Of drug substances, excipients and packaging material either alone or in combinations To guide the formulator to select the right active and inactive ingredients to achieve a stable and desirable formulations
PREFORMULATION
I. Physicochemical properties of the drug substance
Solubility studies Salt screening pKa determination Partition coefficient Crystallization studies Polymorphism studies II. Stability data Chemical stability (accelerated and stress studies) Thermal properties Hygroscopicity (storage conditions) Excipients and packaging compatibility studies III. Early stage formulation Design composition and form according to specifications, dose and bioavailability
PREFORMULATION STUDIES
Preformulation studies are initiated to select Choice of crystalline form (usually stable form, but not always) Choice of particle size (degradation with finer particles but gives better dissolution profile) Choice of vendor (many cases vendor specific impurities) Choice of excipients (some of excipients beneficially or adversely affect the quality of product)
Choice of dosage forms (e.g voriconazole, rabeprazole etc) Choice of storage conditions Choice of manufacturing process Choice of packaging material Two important prerequisite for preformulation studies are Analytical method for detecting physical and chemical degradation Factorial analysis of data
Preformulation studies Method for quantification of active and inactive ingredients Method for solid state characterization of drug substances and drug products Method for characterization of physical properties of dosage forms such as pH, zeta potential, sedimentation, hardness, redesipersibility, friability, moisture up take, clarity and so on Selection of route of administration Selection of dosage form (solid, liquid etc) Selection of special drug delivery system (solubility enhancement, permeability enhancement, enteric dosage forms etc) Data analysis
Analytical methodologies for estimation of drugs and RS some time inactive HPLC method stability indicating method Use PDA detector for rapid method development LC MS incase of structural elucidation of impurities Stability indicating method should be developed Non interference of any inactive ingredients as well un known or new impurities Prior to develop stability indicating method, forced state degradation studies with API alone and in combination with inactive ingredients
CHARACTERIZATION OF POLYMORPHS
Techniques in solid state characterization X ray diffraction - Single crystal XRD - Powder XRD Microscopic techniques - Optical microscopy - Scanning Electron Microscopy - Atomic Force Microscopy Thermal analysis (DSC, TGA, HSM) Spectroscopic studies (FTRI, Raman, ssNMR)
X ray diffraction X rays fall on crystalline phase, there will be diffraction pattern X ray pattern of pure substance is unique and constant and hence it is nothing but finger printing of crystals Mixture of substances, gives its diffraction patent individually
Single Crystal XRD Very difficult to isolate single crystals Precision is very difficult Determination of atomic structure Used to study the Molecule structure, bond angle, type, length PXRD Easy Powder sample is sufficient Non destructive method Identification of drug substances Quantification is possible Identification of impurities in substances
The XRD pattern is a qualitative tool
Whereas intensity of diffraction is quantitative tool
THEORY OF X RAY DIFFRACTION

X rays small part of electromagnetic wavelength () Ranging from 0.02 A-100A Wavelength used is 1A or 2 A Low wavelength hence high energy (Einstein eq E=hc/ ) Wavelength (1 A or 2 A) is similar to the spacing between molecule (1-10 A)

When X ray beam encounter 3 D crystal surface Destructive to each other and net diffraction is nil But in specific direction constructive interference and reinforce each other This reinforce is called as diffraction Diffraction is unique and vary from molecule to molecule Hence used for identification and finger printing of substances The intensity of diffraction is based on the quantity of crystals and hence it is a quantitative tool

In constructive reinforcement Path difference = integral wavelength (integrity is n, wavelength ) Path difference =

Powder diffraction data are usually presented as a diffractogram in which the diffracted intensity I is shown as function either of the scattering angle 2 Diffracted X-rays are detected electronically and recorded Detector rotates simultaneously with the stage, but rotates through angles = 2 theta Thus, the angle 2 theta at which diffractions occur Relative intensities can be read directly from the position and heights of the peaks. High electron density: high diffraction
PHARMACEUTICAL APPLICCATION
PXRD Identification of polymorphs Quantification of polymorphs and mixtures Process optimization Detection of impurities
IDENTIFICATION OF POLYMORPHS CASE STUDY: CBZ
QUANTIFICATION OF POLYMORPHS AND MIXTURES
Quantification is done by Measuring the intensity corresponding to particular polymorph
PROCESS OPTIMIZATION
API batch to batch uniformity in crystalinty Granulation parameter optimization
Effect of temperature on polymorphism of theophylline granules
MICROSCOPIC TECHNIQUES: OM Case study: TY and CBZ
Theophylline anhydrous
CBZ form IIII
MICROSCOPIC TECHNIQUES: SEM Case study: CBZ
MICROSCOPIC TECHNIQUES: HSM Case study: Propylphenazone and NCE

Melting point determination Phase transition (solid solid) Glass transition temperature Can be coupled with FTIR, ssNMR and Raman Thermodynamic stability
Propylphenazone: enatiotropic
Melting of unknown NCE
MICROSCOPIC TECHNIQUES: HSM Case study: CBZ

1
2
D SC mW /mg 0.00
Thermal Analysis Result
Peak
0 173.05x10 C 0 173.55x10 C 0 173.63x10 C 0 -8.19x10 J/g 0 -1.22x10 mW
4
-2.00
File N ame: PU R E D R U G 2008-01-08.tad D etec tor: D SC -60 Ac quis ition D ate 08/01/08 Ac quis ition Time 14:01:21(+0530) Sample N ame: PU R E D R U G Sample W eight:2.670[mg] Annotation:
O nset Endset Heat Height
-4.00
6
-6.00
[Temp Program] Start Temp30.0 Temp R ateH old TempH old Time Gas [C /min ] [C ] [ min ] 10.00 210.0 0 N itrogen
Peak O nset Endset Heat Height
0 190.28x10 C 0 188.50x10 C 0 193.12x10 C 0 -112.90x10 J/g 0 -17. 49x10 mW
50.00
100.00 Temp [C ]
150.00
200.00
THERMAL ANALYSIS: DSC

There are number of thermal analysis used in solid state characterization DSC, TGA and HSM is widely used Type of DSC Heat flux type DSC (Thermocouple; difference in heat transfer) Power compensated type (based on exo or endo thermic event, power compensation) Calorimetric changes and weight changes due to physical or chemical degradation is quantifiable

Method development in DSC is very crucial Analytical heating rate, environment (N2 purging rate), sample pan all the factors influences Method development strategy of NCE REV5901 is mentioned Free base melting endothermic event is not affected by storage conditions and analytical method variation Whereas anhydrous and mono hydrate of HCl salts are have reported with different thermogram based of analytical procedure

Method development strategy of NCE REV5901 is mentioned (free base to be chosen for F&D)
(1) showed no significant change with changes in atmospheric conditions.
For the anhydrous hydrochloride salt (2) on an open pan without purging with N2, (3) in a pan closed by crimping (4) in a hermetically sealed pan For the monohydrate hydrochloride salt (5) on an open pan without purging with N2 (6) on an open pan with purging with N2 (7) in a pan closed by crimping (8) hermetically sealed pan

Exothermic Crystallization Glass transition Endothermic Melting Solid-solid phase transition Dehydration De-solvation
Decomposition

Application Determination of glass transition temperature Melting point Degradation of drug substance Compatibility studies of drug and excipients Polymorphic form identification Degree of crystallinity

Determination of glass transition

Melting point and polymorphic form Identification CBZ form III Melting of form III: Endothermic peak at 171.68 C Crystallization of form I: Exothermic peak at 189.15 C Melting of form I: Endothermic peak at 192.10 C CBZ form I Absence of phase transition at 189.15 C
CBZ (D) Endothermic events at 70-90 C

Compatibility studies of drug and excipients Melting of form III: Endothermic peak at 171.68 C Crystallization of form I: Exothermic peak at 189.15 C Melting of form I: Endothermic peak at 192.10 C Reduction in crystallinty with SD and PM Prevents phase transition No characteristic peak with HPMC

Interaction between ibuprofen and magnesium oxide

Degree of crystallinity Degree of crystallinity is based on heat flux Higher the delta H value, high crystallinity DSC is not a suitable method for determination of low crystalline substances Modulated DSC could be useful

Degradation of active pharmaceutical ingredients e.g Aspirin
IR SPECTROSCOPY
In addition to chemical identification IR is used to differentiate the solid state structures Different arrangement of molecules in different crystals will lead different molecular environment This phenomenon can be used distinguish polymorphic form
IR SPECTROSCOPY
Polymorphs IR peaks
Form I Form II Form III
3464, 1676 and 1383
CM-1
Case Study: CBZ
3484, 1684 and 1397CM-1 3473, 1673, 1393CM-1
OTHER TECHNIQUES IN PREFORMULATION

Diffuse reflectance spectroscopy To detect the solid state interaction between drug substances Isoniazid MgO, interaction decrease the reflectance and increase the content
OTHER TECHNIQUES IN PREFORMULATION

Diffuse reflectance spectroscopy NMR To determine the hydrolysis rate of esters such as atropine Near IR spectroscopy Non destructive analysis of aspirin Polarimetry To estimate the hydrolysis rate of diltiazem
FACTORIAL DESIGN
In formulation development, all the factors are affecting he stability of dosage form Stability of final dosage form is dependent on many complex factors Quantitative role of each factor on stability to be explored It causes very large and complex series of experiment During evaluation of one factor other must be in constant in order to explore the effect
FACTORIAL DESIGN
Factorial analysis usually called as factorial design is a statistical technique to minimize the number of experiment to get a meaningful results Factorial analysis not only results meaningful results but also provide cost effective stable formulation It reduces the developmental time
FACTORIAL DESIGN
Factorial design involves two parameters such as Level of factor Number of factor e.g 2n factorial design, here 2 is the level and n is the number of factor Minimum two levels are required and one can go any number of factors As number of factor and level increases with complexity of experiment
FACTORIAL DESIGN
21 factorial design (two experiments) 22 factorial design (four experiments) 23 factorial design (eight experiments) 31 factorial design (three experiments) 32 factorial design (nine experiments) 33 factorial design (twenty seven experiments) 43 factorial design (sixty four experiments)
FACTORIAL DESIGN
21 factorial design (two experiments) Level is 2 Number of factor is 1 For example effect of HPMC on drug release in CR tablets Here, HPMC is the number of factor, which influence drug release Two levels of 10% and 30% are considered with two different experiment
FACTORIAL DESIGN
22 factorial design (four experiments) Level is 2 Number of factor is 2 For example effect of HPMC and lactose on drug release in CR tablets Here, HPMC and lactose are the number of factors, which influence drug release Level of HPMC is 10% and 30% and level of lactose is 10% and 50% Experiments are 10/10, 10/50, 30/10, 30/50
FACTORIAL DESIGN
23 factorial design (six experiments) Level is 2 Number of factor is 3 For example effect of HPMC, sodium alginate and lactose on drug release in CR tablets Here, HPMC and lactose are the number of factors, which influence drug release Level of HPMC and HEC is 10% and 30% and level of lactose is 10% and 50% Experiments are 10/10/10, 10/10/50, 30/10/10, 30/10/50, 10/30/10, 10/30/50, 30/30/10, 30/30/50
FACTORIAL DESIGN
31 factorial design (three experiments) level 3 Factor 1 Factor is HPMC and effect of three lecl on drug release such as 10, 20 and 30 % on drug release
FACTORIAL DESIGN
32 factorial design (six experiments) Level 3 Factor 2 Two factors such as sodium alginate and HPMC on drug release Level of HPMC is 10, 15 and 20 % and sodium alginate is 5, 10 and 15% Nine different experiment provides optimal composition for best release profiles 10/5, 10/10, 10/15, 15/5, 15/10, 15/15, 20/5, 20/10, 20/15,
FUNCTIONAL CHANGES OF DOSAGE FORM WITH TIME Mechanical strength Drug dissolution from tablets and capsules Melting point of suppositories Drug release from polymeric matrix Drug leaking from liposomes Aggregation of emulsion Moisture adsorption Discoloration Effect of packaging
FUNCTIONAL CHANGES OF DOSAGE FORM WITH TIME
Physical changes in formulation may affect the in vitro drug release Many of these changes are occurred during the storage period Ideal formulation should be stable, and all the physical parameters should be within the limit throughout the shelf life Changes in physical parameters not only affect the invitro drug release but also in vivo release and clinical efficacy
Mechanical strength
Mechanical strength of the solid dosage forms are dependent on humidity and temperature Hydrophobic lubricants such as wax and vegetable oil melt at elevated temperature and causes softening of the tablets Moreover, this waxes, reduce the porosity of the tablet, once it melts, waxes diffuses tablet matrix and fill in the pores of the tablet This leads to pit forming in the surface of the tablets Chances for reduction in drug dissolution time
MECHANICAL STRENGTH
In contrast to hydrophobic low melting excipients, hydrophilic excipients are prone to moisture associated deformalities in mechanical strength Packaging material play an important role in moisture permeability of dosage forms PVP is more permeable, PVdC blisters should be used to pack the moisture sensitive dosage form Highly moisture sensitive drug, HDP bottles with desiccant or glass bottles are highly suitable for moisture sensitive dosage forms A close correlation has been observed with moisture and mechanical strength of the tablets
MECHANICAL STRENGTH
CHANGES IN DRUG DISSOLUTION

Dissolution is an important in vitro characterization of solid orals and suspension dosage forms Example carbamazepine tablets Formation of CBZ dihydate is the reason for reduction in dissolution and hence bioavailability However, invitro dissolution not necessarily to influence the in vivo behavior For example digoxin tablet, upon storage has been reported with lower dissolution than initial value but has no changes in bioavailability

Changes in drug dissolution may be due to various reasons Effect of formulation Change in drug release from coated tablets Change in capsule shell with time and storage conditions Prediction of change in drug dissolution

Effect of formulation Process and formulation ingredients have profound effect on stability of dosage forms during storage period For example phenobarbitone tablets with gelatin as a binder shows decreasing in drug dissolution rate samples stored at 98% RH Dissolution of hydrochlorthiazide tablets with acacia as a binder is increased during storage period at high temperature

Effect of formulation Reduction in bioavailability of nitrofurantoin during storage at high humidity with increased proportion of carbomer in formulation

Effect of formulation Alginic acid used as a tablet disintegrant, high humidity causes decrease in swelling force and reduction in drug dissolution rate Phenytoin capsules are upon storage increased drug dissolution with calcium sulfate and time and decreased with lactose PVP as disintegrant shows storage temperature dependent drug release Solid dispersion with PEG, reduces the drug dissolution time of griseofulvin

Effect of formulation Alginic acid used as a tablet disintegrant, high temperature causes decrease in swelling force and reduction in drug dissolution rate

Change in drug release from coated tablets Stability affect the drug release characteristics of film coated tablets and pellets Film act as a rate limiting step in drug release Curing process of polymeric film affects the drug release Enteric coated and film coated tablets are more prone to humidity than film coated tablets Sugar coated tablets have been reported with change in disintegration time and increases or decreases the drug release Storage time allow cross linking of polymer and hence retard the drug release due high film strength e. g aspirin tablets

Storage time allow cross linking of polymer and hence retard the drug release due high film strength e. g aspirin tablets

Change in capsule shell with time and storage conditions Hard gelatin consists of 12-15% moisture Chloramphenicol tablets stored at high humidity show prolonged disintegration and decreased rug dissolution rate This is probably due to agglomeration of drug particles due to moisture reduce the surface area for dissolution

Change in capsule shell with time and storage conditions Capsules consists of multiple ingredients such as plasticizer, flavor, lubricants so on Drug release may change due to the reaction of capsule shell with content Polysorbate a surfactant used in the capsule get degraded as a formaldehyde, which may aids the cross linking of gelatin Cross linked gelatin capsules result in poor dissolution profile Interaction of dyes and gelatin in presence of light may reduce the drug release

Change in capsule shell with time and storage conditions Acetaminophen tablets coated with gelatin show decreased dissolution in storage Addition of 1% pancreatin restore the drug release profile

Predicting the changes in drug dissolution It is very difficult to mathematically describe the changes in drug dissolution rate during storage period However, some attempts have been made One such example is prednisolone tablets Change in moisture content of the dosage form or components in dosage form changes drug dissolution For example moisture permeability of cellulose acetate film may change the drug dissolution rate
CHANGES IN MELTING TIME OF SUPPOSITORIES

Mechanism for hardening of suppositories Polymorphic transition Crystallization of amorphous wax Trans esterification Even changes in melting point may occur with effervescent suppositories
CHANGES IN DRUG RELEASE RATE

Drug release is different from drug dissolution Drug release is offen associated with not disintegrating systems such as matrix, microcapsules and micro spheres Matrix physicochemical properties and mechanical properties influences the drug release Changes in drug characterization such as polymorphic transition, crystallization and particle growth may have an influence in drug release Changes in glass transition and crystalline state are the two important factors, which affect the drug release kinetics

Molecular weight of the polymer play an important role in drug release Low molecular weight polymers have low mobility of molecules and hence possess lower glass transition temperature Storage at higher temperature leads in increased Tg with PLGA polymer and hence retard the drug release Polymer decomposition during storage not only reduce the Tg but also increase the drug release rate from matrix

Amorphous PLA microspheres loaded with progesterone During storage, crystallization of polymer Results in increased drug release

Storage at temperatures above the Tg increased crystallization, As shown by a diminished exothermic peak in the DSC thermogram recorded following storage, compared to that of a fresh sample
DRUG LEAKAGE FROM LIPOSOMES

During storage, liposomes may exhibit physical instability, leading to leakage ofintraliposomal entrapped drugs. In addition, chemical degradation of lipid membrane components resulting from oxidation and hydrolysis also changes drug release rates from liposomes. For example, phospholipid hydrolysis increased the permeability of a liposome membrane, resulting in increased leakage Drug leakage from liposomes following storage depends on liposomal structure and membrane components Optimization of membrane components and excipients to reduce drug leakage during storage

Liposomes made from egg yolk lecithin exhibited drug leakage following storage However, this effect was reduced by storage at low temperature in an oxygen-free atmosphere or by including antioxidants such as -tocopherol in the formulation Drug leakage was diminished in collagen-containing solutions Collagen produced a decrease in liposome permeability through an antioxidant effect

Aggregation of liposomes upon storage also depends on membrane components. Liposomes that included taurine as an isotonic solute were most stable at an optimal content of benzalkonium chloride
AGGREGATION OF EMULSION
Aggregation is normal physical phenomenon Oxygen-transporting emulsions of perfluorodecalin needed stabilizing additives to prevent aggregation. Increased droplet size is one of the properties of total parental nutrient emulsion during storage Emulsion stability is based on zeta potential of the emulsion Increasing the storage temperature from 25 to 40C markedly reduced the stability of a clofibride emulsion for oral administration, Whereas storage at 4C caused rapid phase separation owing to decreased solubility
Physical stress state stability studies are performed to evaluate the stability of emulsion Ultra-centrifugation, freez thaw cycling, sonication and stress state shaking are used to evaluate the physical stability
MOISTURE ADSORPTION STUDIES

Moisture adsorption by solid dosage forms can result not only in increased chemical drug degradation but also in changes in the functional stability of dosage forms. A hard gelatin capsule exhibited moisture sorption depending on humidity, a monolayer of adsorbed moisture to be distinguished from normal condensation of moisture and from absorption of moisture
DISCOLORATION
Although the discoloration of dosage forms may result from chemical degradation, Mechanisms are usually unclear Discoloration is generally considered to be a physical degradation (degradation of appearance) The changes in discoloration is based on Arrhenius behavior and hence possible to predict the release kinetics
DISCOLORATION
DISCOLORATION
Although the discoloration of dosage forms may result from chemical degradation, Mechanisms are usually unclear Discoloration is generally considered to be a physical degradation (degradation of appearance) The changes in discoloration is based on Arrhenius behavior and hence possible to predict the release kinetics
EFFECT OF PACKING MATERIAL

Actual stability of the drug product is not only based on the final quality of the product but also based on the type and nature of the packaging material Resistance of packaging material to light and moisture significantly improve the stability of dosage forms Stability testing of dosage forms need to be performed with packing material Objective of packing material is to provide aesthetic look and to offer better protection for dosage forms

Packaging material could be affecting Moisture penetration Adsorption Absorption

There is definite link between moisture adsorption and chemical and physical stability of dosage forms Desiccants are often used to eliminate moisture in packaging when the moisture resistance of the packaging itself is not sufficient to prevent exposure. The utility of desiccants has been assessed based on a sorption.desorption moisture transfer model.

Pharmaceuticals may interact with packaging and containers, resulting in the loss of drug substances by adsorption onto and absorption into container components. Incorporation of components of containers into the pharmaceutical product Loss of diazepam by adsorption on glass and absorption in plastic containers Nitroglycerin, a liquid with a significant vapor pressure, is also significantly adsorbed onto and absorbed into containers Absorption of Clomethiazole edisylate and thiopental sodium into PVC infusion bags

pH dependence of adsorption/absorption of acidic drug substances such as warfarin and thiopental and basic drug substances such as chlorpromazine and diltiazem Indicates that only the un-ionized form of the drug substance is adsorbed onto or absorbed into PVC infusion bag Prediction of absorption from partition data is possible Polymers such as nylon 6 (polycaprolactam) are known to adsorb drug substances such as benzocaine

Glass surfaces are also known to adsorb drug substances. Chloroquine solutions in glass containers decreased in concentration owing to adsorption of the drug onto the glass Absorption of preservatives such as chlorocresol into the rubber closures of injectable formulations Adsorption of volatile components from rubber closures onto freeze-dried parenterals during both dosage form processing and storage brought about haze formation upon reconstitution

Leaching of dioctyl phthalate, a plasticizer used especially in PVC plastics, into intravenous solutions containing surfactants
A log-log plot of sorption number ( Sn ) into a PVC container versus octanol-water partition coefficient (Poctanol ) for a number of drugs. Drugs were stored at 15-20C for 1, and 24 h
ESTIMATION OF THE SHELF LIFE

Shelf life is best defined as the time span over which the quality of a product remains within specifications Time period over which the efficacy, safety, and esthetics of the product can be assured Shelf life prediction is based on the prediction of physical and chemical degradation Estimation of shelf life is very difficult When a qualityindicating parameter changes with time via complex kinetics Determination of shelf life should be based on experimental observations Many physical changes are time dependent phenomenon

1. 2. Whereas, estimation of shelf life is relatively easy, if degradation is based on kinetic process Estimation of the product shelf life is done by two methods Extrapolation from real time data Shelf life estimation from temperature accelerated studies

Extrapolation from real time data Woolfe equation has been used to determine the shelf life from the data obtained from the same temperature coditions The time at which the drug product fall on the out of specification is calculated by using the formula

Shelf life estimation from temperature accelerated studies
Shelf life is referred to as t90(T1) when the lower specification limit of content is 90%. Shelf life exhibits a log-linear relationship versus 1/T in a given temperature range when the activation energy is constant The latter condition usually is only met when the degradation mechanism is the same across the temperature range of exposure. For example, a shelf life of 6 months at 40C corresponds to a shelf life of 3 years at 25C when an activation energy of 22.1 kcal/mol is assumed
CHEMICAL STABILITY OF DRUG SUBSTANCES

Most studied and easily understood drug instability is chemical instability Chemical instability leads loss of drug in dosage forms And hence leads loss of potency and subsequently therapeutic failure In some cases, drug product may produce toxic substances, which leads ADRs Most of the degradation are pH dependent and some of them accelerated by temperature, moisture, oxygen and light Example are praldoxime, tetracycline and penicillin
Degradation may affect the aesthetic look of the formulation Degradation may change the color, odor and taste of the formulation Example ephedrine to adrenochrome causes intense red color

Unknown degradation of unknown drug results volatile, sulfur containing compounds with bad odor Many drug substances are stable in neutral pH, but which are degrading at acidic pH in stomach or formulations e.g erthromycin Even small quantity of drug degradation may affect the physical and chemical stability

Chemical degradation may occur in different pathways such as Hydrolysis Dehydration Isomerization and racemization Decarboxylation and elimination Oxidation Photo degradation Drug drug interaction Drug excipient interaction

Hydrolysis Is most common pathway of drug degradation parenteral dosage forms as well as solid dosage forms Most common reaction occurred in pharmaceutical products Ester and amide functional groups have more prone for hydrolysis Examples are aspirin, procaine, Chloramphenicol, atropine and so on

Hydrolysis Esters (carboxylic acid ester, carbamic acid esters) Amides Hydantoins, barbiturates and imides Reaction involved in C-N Cleavage Other hydrolytic reactions

Hydrolysis: Esters
Many drug substances contain an ester bond Traditional esters are those formed between a carboxylic acid and various alcohols Other esters formed between carbamic, sulfonic, and sulfamic acids and various alcohols These ester compounds are primarily hydrolyzed through nucleophilic attack of hydroxide ion and/or water at the ester

Hydrolysis: Esters Degradation rate depends on the substituents Electron-withdrawing groups enhance hydrolysis (X, CN, CO, NO2) Whereas electron-donating groups inhibit hydrolysis (Alkyl, Amino, alcohol) Substituted benzoates having an electron-withdrawing group, such as a nitro group exhibit higher decomposition rates than the unsubstituted benzoate Decomposition rate decreases with increasing electron-donating effect of the alkyl group (in the alcohol portion of the ester(R2)) (e.g., it decreases in the order methyl > ethyl > n-propyl)

Hydrolysis: Esters Electron leaving ability determines the rate of hydrolysis Example ethyl benzoate degrades faster that phenyl benzoate Ethyl group will be discharged rapidly to build electronegative charge of oxygen atom Stearic factor play an important role in hydrolysis Substitution of IPA group is five times faster hydrolysis rate than n propyl substitution

Parallel pathways in hydrolysis If molecule have two ester group, hydrolysis may occur in both groups, and results with two different degradation products

Hydrolysis: Esters From structure, one can predict the hydrolysis For example, if two molecules have similar structure, we can predict hydrolysis rate from one to another E.g ethyl paraben and benzocaine pH dependent hydrolysis of atropine and scopalamine This data will be useful to determine the rate hydrolysis of NCEs by proper literature search

Hydrolysis: Esters Lactones, or cyclic esters, also undergo hydrolysis e.g. Pilocarpine, Dalvastatin, warfarinand and camptothecin Exhibit ring opening due to hydrolysis Note Unlike linear esters, lactones often exist in dynamic equilibrium with their carboxylic acid/carboxylate forms

Hydrolysis: Esters

Hydrolysis: Esters Rate of hydrolysis is dependent on Structure (predominantly) Temperature Ionic strength Buffering capacity pH of the medium Physical state

Hydrolysis: Esters Carbamic acid hydrolysis Carbmates undergo hydrolysis at strong acidic and neutral to alkaline pH conditions e.g chlorphenesin carbamate and carmethizole Sulfonic acid and sulfamic acid undergo hydrolysis Via C-O cleavage than C-S cleavage

Hydrolysis: Esters Sulfonic acid and sulfamic acid undergo hydrolysis

Hydrolysis: Esters Carbamic acid hydrolysis

Hydrolysis: Amide Amide bonds are commonly found in drug molecules Amide bonds are less susceptible to hydrolysis than ester bonds Because the carbonyl carbon of the amide bond is less electrophilic (the carbon-to-nitrogen bond has considerable double bond character) and the leaving group, an amine, is a poorer leaving group

Hydrolysis: Amide Example acetaminophen, chloramphenicol, lincomycin, Indomethacin sulfacetamide

Hydrolysis: Amide Moricizine, a derivative of phenothiazine, which undergoes hydrolysis of its amide bonds followed by oxidation HI-6, a bis(pyridimium)aldoxime having an amide bond, which exhibits fast hydrolysis In concentrated aqueous solutions owing to the acidifying effect of a strongly acidic oxime group

Hydrolysis: Amide Moricizine, a derivative of phenothiazine, which undergoes hydrolysis of its amide bonds followed by oxidation HI-6, a bis(pyridimium)aldoxime having an amide bond, which exhibits fast hydrolysis In concentrated aqueous solutions owing to the acidifying effect of a strongly acidic oxime group

Hydrolysis: Amide -Lactam antibiotics such as penicillins and cephalosporins, which are cyclic amides or lactams, undergo rapid ring opening due to hydrolysis Ring opening of the -lactam such as penams and cephems Penams benzylpenicillin, ampicillin, amoxicillin, carbenicillin, phenethicillin and methicillin Cephems Cephalothin, cefadroxil, cephradine, and cefotaxime

Hydrolysis: Amide

Hydrolysis: Amide

Hydrolysis: Amide Barbiturates, hydantoins, and imides contain functional groups related to amides But tend to be more reactive. Barbituric acids such as Barbital Phenobarbital Amobarbital metharbital undergo ring-opening hydrolysis Degraded product further undergoes decomposition reaction such as decarboxylation

Hydrolysis: Other chemical groups such as hydantoins, benzodiazipines and chlordiazepoxides undergoes hydrolysis

Hydrolysis: benzodiazipines

Hydrolysis: benzodiazipines Schiff Base

Hydrolysis: Schiff Base

Hydrolysis: other hydrolysis Alkyl halides such a clindamycin and azathioprine Sulfides such as thiomersol Platinum compounds such as carboplatin Carbohydrate moieties such as digoxin eliminates carbohydrate groups by acid hydrolysis

Hydrolysis: other hydrolysis



Dehydration Sugars such as glucose and lactose are undergo dehydration to form furural Erthromycin is subject to acid hydrolyzed dehydration PG E1 and E2 dehydration followed by isomerization Streptovitacin exhibits two successive acid catalyzed dehydration

Dehydration

Dehydration

Dehydration

Decarboxylation

Oxidation Oxidation is a well-known chemical degradation pathway for pharmaceuticals. Oxygen, which participates in most oxidation reactions, Is abundant in the environment to which pharmaceuticals are exposed, during either processing or long-term storage

Oxidation

Oxidation

Oxidation

Photo degradation

In the presence of drug substances with hydroxy groups, aspirin undergoes a reversible transacylation reaction to form salicylic acid, while acetylating the drug substance

Factors determining the chemical stability of drug substances includes intrinsic factors e.g molecular structure of the drug itself and environmental factors e.g. temperature, pH, buffer species, ionic strength, light, oxygen, moisture, additives, and excipients.

In the case of solid-state degradation, the solid-state properties of the drug such as melting point, crystallinity, and hygroscopicity are very important. In addition, mechanical forces such as pressure and grinding applied to drug substances may affect their chemical as well as physical stability By applying well-established kinetic concepts, it is possible not only to summarize, numerically, the role that each variable might play in altering the kinetics of degradation but also to provide valuable insight into the mechanism(s) of degradation

Basic Kinetic Principles The simplest concept of chemical and physical reaction is the case of a drug D reacting to form a product P. This process is described by the following scheme:
The extent to which D rearranges to P will depend on the free-energy differences between D and P. If P is of much lower free energy than D, then the reaction is better defined by

Basic Kinetic Principles Most drugs degrade by reactions that involve a so-called bimolecular reaction in which drug D collides with a reactant A to produce one or more products. This is illustrated in its simplest form by the following equation:
D+A=P
P will be formed if D and A collide with sufficient energy (and an appropriate orientation) to result in a molecular rearrangement to form P. In this simple case, the rate of loss of D, -d[D]/dt, is said to be proportional to the activity (or, more simply, the concentration) of both D and A, as indicated by Eq.

Basic Kinetic Principles

Basic Kinetic Principles
The Role of Molecular Structure

Molecular structure of a drug substance determines its degradation mechanisms/pathways Substituents around the reaction center can strongly influence its reactivity. For example, a drug substance having an electronwithdrawing functional group close to an ester bond will probably exhibit a higher propensity to nucleophilic attack by hydroxide ion than will a similar ester without that functional group.

The Role of Molecular Structure The increased rate of degradation can be explained by assuming that the electron-withdrawing group makes the carbonyl carbon of the ester group more susceptible to attack, as well as stabilizing the formed activated complex, thus decreasing G Increased rate of reaction with increased delta G Decreased hydrolysis rate of esters with bulky substituents near the ester group can be explained in terms of an increased G.. Steric factors can be significant for many chemical reactions. Consider the lactonization of isopilocarpic acid and pilocarpic acid to isopilocarpine and pilocarpine

Effect of temperature Temperature is one of the primary factor influences rate constant and hence rate of reaction
Quantitative relationship between temperature and rate constant as follows

Effect of temperature

Effect of pH Major factor for drug degradation Water is critical reactant for pH dependent degradation Hydrogen ion and hydroxyl ion concentration is based on the pH

Effect of buffers Buffers are used to stabilize the pH and hence improve the stability of the formulation However, buffers are also responsible for drug degradation E.g catalysis of chloramphenicol degradation by acetate buffer and phosphate buffer.

Effect of ionic strength Drug degradation reaction is between ionic species Presence of ionic species such as sodium chloride affect the drug substances. E.g. rate of hydrolysis of thiamine

Effect of dielectric constant of solvent Rate reaction of ionic species and dipoles is dependent on bulk properties of solvent Dielectric constant is one the important bulk property Rate reaction is dependent on dielectric constant
Effect of changes in solvent dielectric constant on the degradation rate of chloramphenicol in the presence of perchloric acid

Effect of oxygen The kinetics of the oxidation of drug substances can be affected by the availability of oxygen. Some photodegradation reactions involve photooxidative mechanisms that are dependent on oxygen concentration. An example is the increased photodegradation of cianidanol with increasing oxygen concentration Oxygen is a reactant and hence alter the rate kinetics Rate of oxidation of ascorbic acid is an example for oxygen concentration dependent degradation

Effect of oxygen Oxygen exists in various states. In its ground state, oxygen exists as a diradical or triplet oxygen, but it can be excited by light to singlet oxygen Singlet oxygen is highly oxidizing and capable of attacking olefinic bonds. Oxygen can also form other oxidizing species Superoxide species is a mild reductant whereas hydrogen peroxide is a fairly specific oxidant. The hydroxyl radical is highly reactive but has low selectivity

Effect of oxygen e.g. ascorbic acid oxidation

Effect of light
Wave length and number of incidence photon is crucial for photo degradation Quantitative degradation is very difficult Wave length associated quantitative relationship is well established e.g. Nifidipine

Effect of crystalline state
Free energy is dependent on crystalline state Hence it affects the chemical degrdation Vitamin A derivative there is a inverse relation ship is obtained between melting point and degradation

Effect of moisture content
Moisture act as plasticizer and hence enhances the molecular mobility for reaction It act as reactant medium As a reactant Free water/crystalline water/bounded water
Effect of water content on the degradation of vitamin A tablets

Stability of drug substances Molecular structure modification (e.g. erthro vs clarithro) Complex formation Inclusion complexation Incorporation (liposomes, micelles, emulsions) Addition of anti oxidant Packing material as stabilizer

Stability Studies:: Pharmaceutical Product Development

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STABILITY STUDIES:

PHARMACEUTICAL PRODUCT DEVELOPMENT

GUNDA NAREH Khammam College O f Pharmacy 09000060616

NATURE AND TYPE OF DOSAGE FORM

NATURE AND TYPE OF DOSAGE FORM

STABILITY PROTOCOL: BATCHES

STABILITY PROTOCOL: BATCHES

STABILITY PROTOCOL: CONTAINERS

STABILITY PROTOCOL: OREINTATION OF CONTAINERS

STABILITY PROTOCOL: SAMPLING POINT

STABILITY PROTOCOL: SAMPLING POINT

STABILITY PROTOCOL: SAMPLING PLAN

STABILITY PROTOCOL: STORAGE CONDITIONS

STABILITY PROTOCOL: TESTING PARAMETER

STABILITY PROTOCOL: TESTING METHODOLOGIES

STABILITY PROTOCOL: ACCEPTANCE CRITERIA

CRYSTALLINE STATE TRANSITION

VAPOR PHASE TRANSFER

VAPOR PHASE TRANSFER

EFFECT OF WATER ON SOLIDS

KINETICS OF SOLID PHASE TRANSITIONS

KINETICS OF SOLID PHASE TRANSITIONS

KINETICS OF SOLID PHASE TRANSITIONS

STABILITY OF DOSAGE FORMS

STABILITY OF DOSAGE FORMS

STABILITY OF DOSAGE FORMS

STABILITY OF DOSAGE FORMS

STABILITY OF DOSAGE FORMS

STABILITY OF DOSAGE FORMS

STABILITY OF DOSAGE FORMS

STABILITY OF DOSAGE FORMS

The XRD pattern is a qualitative tool

Whereas intensity of diffraction is quantitative tool

THEORY OF X RAY DIFFRACTION

THEORY OF X RAY DIFFRACTION

THEORY OF X RAY DIFFRACTION

THEORY OF X RAY DIFFRACTION

IDENTIFICATION OF POLYMORPHS CASE STUDY: CBZ

QUANTIFICATION OF POLYMORPHS AND MIXTURES

Quantification is done by Measuring the intensity corresponding to particular polymorph

MICROSCOPIC TECHNIQUES: OM Case study: TY and CBZ

CBZ form IIII

MICROSCOPIC TECHNIQUES: SEM Case study: CBZ

MICROSCOPIC TECHNIQUES: HSM Case study: Propylphenazone and NCE

Melting of unknown NCE

MICROSCOPIC TECHNIQUES: HSM Case study: CBZ

Thermal Analysis Result

0 173.05x10 C 0 173.55x10 C 0 173.63x10 C 0 -8.19x10 J/g 0 -1.22x10 mW

O nset Endset Heat Height

Peak O nset Endset Heat Height

0 190.28x10 C 0 188.50x10 C 0 193.12x10 C 0 -112.90x10 J/g 0 -17. 49x10 mW

THERMAL ANALYSIS: DSC

THERMAL ANALYSIS: DSC

THERMAL ANALYSIS: DSC

THERMAL ANALYSIS: DSC

THERMAL ANALYSIS: DSC

THERMAL ANALYSIS: DSC

THERMAL ANALYSIS: DSC

CBZ (D) Endothermic events at 70-90 C

THERMAL ANALYSIS: DSC

THERMAL ANALYSIS: DSC

THERMAL ANALYSIS: DSC

THERMAL ANALYSIS: DSC