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Seminar on

                  POLYMORPHISM
           (AS A PART OF PREFORMULATION STUDY)

           Guided by :              Prepared by :
           Mrs. Hiral Shah          Henil Patel
           Assistant Professor      M.Pharm Sem 1
           Dept. Of Pharmaceutics   Pharmaceutics.




2/1/2013                                             1
List of contents

1.     Definition
2.     Need to study polymorphism ( rational for selecting polymorph)
3.     Properties
4.     Types of polymorphism
5.     How to differentiate them
6.     Pseudopolymorphism.
7.     Method for identify polymorphism
8.     Parameter to be cared by preformulator
9.     Factor affecting polymorphism
10.    Effect of polymorphism on bioavailability
11.    Application
12.    Conclusion
13.    references
2/1/2013                                                                2
Definition
  When a substance exists in more than one crystalline form, the different form
   are designated as polymorphs and the phenomenon as polymorphism.

e.g.:-
• carbon: diamond in a cubic ( tetrahedral lattice arrangement )
• Graphite in sheet of a hexagonal lattice.




2/1/2013                                                                      3
Cont…


Thus it is defined as the ability of substance to exist as two or more
  Crystalline phase that have different Arrangements or conformations of
  the molecule in the crystallatice .




2/1/2013                                                               4
Need to study polymorphism
• Depending upon their relative stability, one of the several polymorphic
  form will be physically more stable than others.
• Stable polymorph represent s the lowest energy state, has highest
  melting point and least aqueous solubility.
• Metastable form represent the higher energy state, have lower melting
  point and high aqueous solubility .
• Metastable form converted to the stable form due to their higher energy
  state.
• Metastable form shows better bioavailability and therefore preferred in
  formulations.
• Only 10% of the pharmaceuticals are present in their metastable form.
                                                                  Cont..


2/1/2013                                                                5
• Polymorphism is remarkably common particularly within certain structural
  group.
• E.g. –
                      CLASS           %OF POLYMORPHISM
           Barbiturates               63
           Steroids                   57
           Sulphonamides              40

                                                                   Cont..



2/1/2013                                                                 6
• The effect of polymorphism on bioavailability is the most important
   consequence for drug substance if the bioavailability is mediated via
   dissolution.
• The example is chloramphenicol palmitate.
• Other like novobiocin , griseofulvine , Carbamazepine , aspirin and
   ampicilline .
• The polymorphism of the excipients may also play an important role in
   bioavailability.
Latest example is :- HYDOISOINDOLIN
                     ( a tachykinine receptor antagonist )
                                                                 Cont..




2/1/2013                                                               7
Stability characteristics

• Depending upon relative stability there are two form of polymorphs 1)
  stable form 2) meta form .
• Stable form having least aqueous solubility.
• Meta form having high aqueous solubility.
• Solubility ratio =solubility of metastable form/solubility of stable form.
• From below example, we can say that solubility ratio is higher than one just
  because of …
• relative higher solubility of metastable form, that leads to increase
                                                                           Cont..




2/1/2013                                                                        8
Compound                 Solubility ratio
glybuzole(37)            1
Tetracycline             1
Carbamazepine            1.2
Succynil sulfathiazole   12.7
Niclosamide              22.9


                                            Cont..




2/1/2013                                        9
Dissolution behavior of the polymorphs

• the absorption rate and bioavailability of drug administered orally is
  controlled by many factor.

•     among which dissolution rate is one of the most important.

•    as the thermodynamic activity of polymorph is lower there is lower
    apparent solubility and thus absorption is also less.

• Order of dissolution rate: Amorphous>metastable> stable


                                                                   cont..



2/1/2013                                                                    10
FORMATION OF METASTABLE POLYMORPHS:-

•    Preparation of metastable polymorphs requires,
•    Supersaturating conditions for the metastable form.
•    Crystallization of the metastable state before the stable polymorph forms.
•    Stable conditions for the metastable polymorph so that conversion to the
    stable form is prevented .




2/1/2013                                                                     11
Properties of polymorphs
Polymorphs show the same properties in the liquid or gaseous state but they
behave differently in solid state.
 Melting and sublimation temperature.
 Vapour pressure
 Solubility and dissolution rate
 Stability
 Optical and electrical property
 Crystal habit
 Hygroscopicity
 Heat capacity
 Solid-state reaction
 Conductivity
 Compression characteristics
2/1/2013                                                                      12
Type of polymorphism
                    TYPE
1. ENANTIOTROPIC POLYMORPH




2. MONOTROPIC POLYMORPH




2/1/2013                          13
• Phase transition: the process of transformation of one polymorph into
  another.
• which may also occur on storage or during processing, is called phase
  transition.

• ENANTIOTROPHS:- If one form stable over certain pressure and
  temperature range, while the other polymorph is stable over different
  pressure and temperature range.

•    eg, sulfur




2/1/2013                                                             14
• MONOTROPHS:- only one polymorph is stable at all temperature below
  the melting point, with all other polymorph being unstable.
• E.g. glyceryl stearate , chloramphenicol palmitate .

 Both enantiotropism and monotropism are important properties of
  polymorphs.




2/1/2013                                                               15
Difference between enantiotropy and monotropy.

     Enantiotropic pair                      monotropic pair
    Reversible phase transition            Irreversible phase transition
    Metastable           stable            Metastable      stable
    Transition is endothermic              Transition is exothermic
    Lower melting form is                  Higher melting form is always
    thermodynamically stable below the     thermodynamically stable form.
    transition temp.. And higher m.p .
    form is stable above the transition
    temp..

    lower m.p. has lower heat of fusion.   Higher m.p. has high heat of fusion.




2/1/2013                                                                     16
PSEUDOPOLYMORPHISM
• Term - pseudo means = false

• The phenomenon in which solvent molecules get incorporated into crystal
  lattice of solid are known as solvates.

• This solvates exist in different crystal form called pseuodopolymorph and
  the phenomenon is called as Pseudopolymorphism .

•    also known as a hydrate when water is solvent.

• E.g.- synthetic estrogen ‘ethynylestradiol ’ is crystallized from the solvent
  acetonitrile , methanol , chloroform and saturated with water four different
  crystalline solvates are form.


2/1/2013                                                                     17
Differentiate pseudopolymorph form true polymorph.

• By observing melting behavior in silicon oil using hot stage microscopy.
• Here in this technique pseudopolymorph evolve the gas causing bubbling
  of the oil.
• While true polymorphs merely melts, forming second globular phase.




2/1/2013                                                                     18
Method to identify polymorphism
Optical crystallography:
• Use in the identification of polymorphs crystal exist in isotropic and
  anisotropic form
• Isotropic examine the velocity of light is same in all direction
• Anisotropic crystal have 2 or3 different light velocities or refractive
  indices.
• Video recording system and polarizing microscope fitted during according
  to heating and cooling stage for investigating polymorph.
                                                            cont…




2/1/2013                                                                     19
APPLICATION
•   To study of degree of stability of metastable form.
•   Transition temperature
•   Melting point
•   Rate of transition under various thermal and physical condition.
•   Whether to peruse polymorphism as a route to an improved dosage form.




2/1/2013                                                                    20
Hot stage microscopy

• Fluid stage transformation as a function of temperature is observed
• Silicon oil stage microscopy is used for detection of pseudopolymorph.
  APPLICATION:
• in the study of solid-state active pharmaceutical ingredients
  (APIs), EXCIPIENTS and pharmaceutically relevant polymers and lipids.




2/1/2013                                                              21
x ray diffraction method

•   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.

• In an X-ray diffraction measurement, a crystal is mounted on a goniometer
  and gradually rotated while being bombarded with X-rays, producing a
  diffraction pattern of regularly spaced spots known as reflections.

• It is tedious time consuming so it is not used or unsuitable for routine use.

2/1/2013                                                                          22
Application:-
• many materials can form crystals—such as salts, metals, minerals,
  semiconductors, as well as various inorganic, organic and biological
  molecules—X-ray crystallography has been fundamental in the
  development of many scientific fields




2/1/2013                                                            23
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.
• A DTA consists of a sample holder comprising thermocouples, sample
  containers and a ceramic or metallic block; a furnace; a temperature
  programmer; and a recording system.
• The key feature is the existence of two thermocouples connected to a
  voltmeter.
• One thermocouple is placed in an inert material such as Al2O3, while the
  other is placed in a sample of the material under study.
• As the temperature is increased, there will be a brief deflection of the
  voltmeter if the sample is undergoing a phase transition.


2/1/2013                                                                24
Differential Scanning Calorimetric (DSC)

•    DSC 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.

•   Samples     that      may      be     studied     by    DSC      or   DTA     are:
    Powders, fibers , single crystals, polymer films, semi-solids.

•   DSC measures endothermic and exothermic transitions as a function of
    temperature.

•   –Endothermic heat flows into a sample.

•   –Exothermic heat flows out of the sample.

2/1/2013                                                                            25
Differential
           Scanning
           Calorimeter
           (TA Instruments
           Q10, Q 100,Q
           1000)




2/1/2013               26
Applications of DTA / DSC in preformulation studies


   1. 1. To determine the purity of a sample
      2. To determine the number of polymorphs and to determine
      the ratio of each polymorph
      3. To determine the heat of solvation .
      4. To determine the thermal degradation of a drug or
      excipients .
      5. To determine the glass-transition temperature(tg) of a
      polymer.




2/1/2013                                                    27
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
  measurements: weight and temperature change.

• As many weight loss curves look similar, the weight loss curve
  may require transformation before results may be interpreted.




2/1/2013                                                           28
• 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.
• TGA Q 500.




2/1/2013                                                                    29
Dilatometry

• Measure change in volume caused by thermal or chemical effect.
• Using dilatometry the melting behaviour of Theobroma Oil was studied.
• Extremely accurate but tedious , time consuming and not widely used.




2/1/2013                                                                  30
Melting point

• M.P. determination are often useful technique, but only when substance
  undergoing investigation heated through phase transition without
  decomposition.




2/1/2013                                                              31
Parameter to checked by preformulator
1.     No of polymorphs
2.     Relative degree of stability
3.     Presence of glassy state
4.     Stabilization of metastable form
5.     Temperature stability range
6.     Solubility of each polymorph
7.     Method of preparation
8.     Effect of micronization
9.     Excipients incompatibility




2/1/2013                                  32
Factor affecting polymorphism

A) Temperature and Humidity:-
•     Storage conditions affect physicochemical reaction which are accelerated
      at higher temperature.
•     Humidity acts as a catalyst on the solid surface.
•     E.g.
1.    Zanoterone the solid degradation rate of form 4 is found to be greater
      than that of form 3 at 40 C/ 25 %RH and 40 C/75% RH. At 40 C/ 25
      %RH , the rate of degradation is 4 fold higher for form 4 vs 3.
2.    Polymorphic transformation of cocoa butter occur after heating.




2/1/2013                                                                    33
B) Photostability

• Generally light sensitive drug are protected form the photolytic degradation
   by packing them suitable in light resistant container.
• Stable crystalline form resist photochemical degradation and does not
   require light resistant system.
E.g.
1) Acetametacin alpha, beta – stable
                    gamma - unstable.




2/1/2013                                                                    34
C) Effect of solvent

• Solvent can bring dramatic change in growth mechanism and morphology.
• Kinetic of crystal growing form solution was determined by two important
  factors.
           a. degree of molecular roughness
           b. nature of absorption of the solvent from surface.




2/1/2013                                                                35
D) Effect of grinding

• Grinding process reduces particle size, so increasing specific surface area
  and that why direct effect on dissolution rate and bioavaibility of the
  formulation.

• During process solid state polymorphic transformation in to non crystalline
  or metastable form is caused by mechanical action.

• E.g.- dihydrate form is more stable than anhydrous form. With increasing
  grinding time compound become unstable because grinding weakened
  bonding crystals and water molecules.




2/1/2013                                                                   36
E) Effect of tablet compression:-

• Stability and compaction behavior form of of the polymorphic form of
  drug is important
• Phenylbutazone in which form 3 converted to 2 form at >2000kg/cm2.




2/1/2013                                                            37
Effect of polymorphism on
                  bioavailability
 If the absorption of active ingredient in drug through G.I.T. is dissolution
  rate dependent then polymorphism is an important preformulation tool.


    Here successful utilization of polymorph having significant greater
    thermodynamic activity (solubility)may provide good therapeutic blood
    level from otherwise inactive drugs. Eg novobiocin .



 two different forms : crystalline and amorphous. In tablet or capsule
  formulation

 novobiocin is used as sodium salt which is active orally but unstable
  chemically while insoluble form is stable chemically and orally
  inactive.(unabsorbable )



2/1/2013                                                                    38
APPLICATION
1.    The knowledge of solid-state properties in an early stage of drug development helps to
      avoid manufacturing problems, to fine-tune the performance of drugs and provides space
      for innovations .
e.g.- Famotidine which is an excellent histamine
      H2 receptor antagonist is also found to exist in two different polymorphic forms,
      metastable polymorph B and stable polymorph A.

2.     For improvement of therapeutic activity of drug.

3.     To prevent loss of raw material.

4.     For better bioavailabity of drug.




.




2/1/2013                                                                                       39
Conclusion
• Differences in the solubility and melting point must also be assessed and
  then a decision can be made to determine which form to progress through
  to the next stage.
• Metastable form may lead to a preferential choice of a polymorph other
  than sable form .
• As polymorphism can have such serious consequences for the
  bioavailability of drugs with low aqueous solubility.




2/1/2013                                                                 40
Study Question
1.     What is polymorphism? Discuss its significance in dissolution.
       Enumerate the methods to identify polymorphs. 6 mark ( GTU July
       2012 )




2/1/2013                                                                 41
References
1.     The theory and practice of industrial pharmacy by- Leon Lechman ,
       Joseph L Kanig .
2.     Biopharmaceutics and pharmacokinetics by- DM Bhramankar , Sunil
       Jaiswal .
3.     Physical pharmacy by- Alfred Martine.
4.     The science of dosage form design by Michael E Alton .
5.     Encyclopedia of pharmaceutical technology .




2/1/2013                                                              42
Thank you



2/1/2013               43

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Seminar on polymorphism

  • 1. Seminar on POLYMORPHISM (AS A PART OF PREFORMULATION STUDY) Guided by : Prepared by : Mrs. Hiral Shah Henil Patel Assistant Professor M.Pharm Sem 1 Dept. Of Pharmaceutics Pharmaceutics. 2/1/2013 1
  • 2. List of contents 1. Definition 2. Need to study polymorphism ( rational for selecting polymorph) 3. Properties 4. Types of polymorphism 5. How to differentiate them 6. Pseudopolymorphism. 7. Method for identify polymorphism 8. Parameter to be cared by preformulator 9. Factor affecting polymorphism 10. Effect of polymorphism on bioavailability 11. Application 12. Conclusion 13. references 2/1/2013 2
  • 3. Definition When a substance exists in more than one crystalline form, the different form are designated as polymorphs and the phenomenon as polymorphism. e.g.:- • carbon: diamond in a cubic ( tetrahedral lattice arrangement ) • Graphite in sheet of a hexagonal lattice. 2/1/2013 3
  • 4. Cont… Thus it is defined as the ability of substance to exist as two or more Crystalline phase that have different Arrangements or conformations of the molecule in the crystallatice . 2/1/2013 4
  • 5. Need to study polymorphism • Depending upon their relative stability, one of the several polymorphic form will be physically more stable than others. • Stable polymorph represent s the lowest energy state, has highest melting point and least aqueous solubility. • Metastable form represent the higher energy state, have lower melting point and high aqueous solubility . • Metastable form converted to the stable form due to their higher energy state. • Metastable form shows better bioavailability and therefore preferred in formulations. • Only 10% of the pharmaceuticals are present in their metastable form. Cont.. 2/1/2013 5
  • 6. • Polymorphism is remarkably common particularly within certain structural group. • E.g. – CLASS %OF POLYMORPHISM Barbiturates 63 Steroids 57 Sulphonamides 40 Cont.. 2/1/2013 6
  • 7. • The effect of polymorphism on bioavailability is the most important consequence for drug substance if the bioavailability is mediated via dissolution. • The example is chloramphenicol palmitate. • Other like novobiocin , griseofulvine , Carbamazepine , aspirin and ampicilline . • The polymorphism of the excipients may also play an important role in bioavailability. Latest example is :- HYDOISOINDOLIN ( a tachykinine receptor antagonist ) Cont.. 2/1/2013 7
  • 8. Stability characteristics • Depending upon relative stability there are two form of polymorphs 1) stable form 2) meta form . • Stable form having least aqueous solubility. • Meta form having high aqueous solubility. • Solubility ratio =solubility of metastable form/solubility of stable form. • From below example, we can say that solubility ratio is higher than one just because of … • relative higher solubility of metastable form, that leads to increase Cont.. 2/1/2013 8
  • 9. Compound Solubility ratio glybuzole(37) 1 Tetracycline 1 Carbamazepine 1.2 Succynil sulfathiazole 12.7 Niclosamide 22.9 Cont.. 2/1/2013 9
  • 10. Dissolution behavior of the polymorphs • the absorption rate and bioavailability of drug administered orally is controlled by many factor. • among which dissolution rate is one of the most important. • as the thermodynamic activity of polymorph is lower there is lower apparent solubility and thus absorption is also less. • Order of dissolution rate: Amorphous>metastable> stable cont.. 2/1/2013 10
  • 11. FORMATION OF METASTABLE POLYMORPHS:- • Preparation of metastable polymorphs requires, • Supersaturating conditions for the metastable form. • Crystallization of the metastable state before the stable polymorph forms. • Stable conditions for the metastable polymorph so that conversion to the stable form is prevented . 2/1/2013 11
  • 12. Properties of polymorphs Polymorphs show the same properties in the liquid or gaseous state but they behave differently in solid state.  Melting and sublimation temperature.  Vapour pressure  Solubility and dissolution rate  Stability  Optical and electrical property  Crystal habit  Hygroscopicity  Heat capacity  Solid-state reaction  Conductivity  Compression characteristics 2/1/2013 12
  • 13. Type of polymorphism TYPE 1. ENANTIOTROPIC POLYMORPH 2. MONOTROPIC POLYMORPH 2/1/2013 13
  • 14. • Phase transition: the process of transformation of one polymorph into another. • which may also occur on storage or during processing, is called phase transition. • ENANTIOTROPHS:- If one form stable over certain pressure and temperature range, while the other polymorph is stable over different pressure and temperature range. • eg, sulfur 2/1/2013 14
  • 15. • MONOTROPHS:- only one polymorph is stable at all temperature below the melting point, with all other polymorph being unstable. • E.g. glyceryl stearate , chloramphenicol palmitate .  Both enantiotropism and monotropism are important properties of polymorphs. 2/1/2013 15
  • 16. Difference between enantiotropy and monotropy. Enantiotropic pair monotropic pair Reversible phase transition Irreversible phase transition Metastable stable Metastable stable Transition is endothermic Transition is exothermic Lower melting form is Higher melting form is always thermodynamically stable below the thermodynamically stable form. transition temp.. And higher m.p . form is stable above the transition temp.. lower m.p. has lower heat of fusion. Higher m.p. has high heat of fusion. 2/1/2013 16
  • 17. PSEUDOPOLYMORPHISM • Term - pseudo means = false • The phenomenon in which solvent molecules get incorporated into crystal lattice of solid are known as solvates. • This solvates exist in different crystal form called pseuodopolymorph and the phenomenon is called as Pseudopolymorphism . • also known as a hydrate when water is solvent. • E.g.- synthetic estrogen ‘ethynylestradiol ’ is crystallized from the solvent acetonitrile , methanol , chloroform and saturated with water four different crystalline solvates are form. 2/1/2013 17
  • 18. Differentiate pseudopolymorph form true polymorph. • By observing melting behavior in silicon oil using hot stage microscopy. • Here in this technique pseudopolymorph evolve the gas causing bubbling of the oil. • While true polymorphs merely melts, forming second globular phase. 2/1/2013 18
  • 19. Method to identify polymorphism Optical crystallography: • Use in the identification of polymorphs crystal exist in isotropic and anisotropic form • Isotropic examine the velocity of light is same in all direction • Anisotropic crystal have 2 or3 different light velocities or refractive indices. • Video recording system and polarizing microscope fitted during according to heating and cooling stage for investigating polymorph. cont… 2/1/2013 19
  • 20. APPLICATION • To study of degree of stability of metastable form. • Transition temperature • Melting point • Rate of transition under various thermal and physical condition. • Whether to peruse polymorphism as a route to an improved dosage form. 2/1/2013 20
  • 21. Hot stage microscopy • Fluid stage transformation as a function of temperature is observed • Silicon oil stage microscopy is used for detection of pseudopolymorph. APPLICATION: • in the study of solid-state active pharmaceutical ingredients (APIs), EXCIPIENTS and pharmaceutically relevant polymers and lipids. 2/1/2013 21
  • 22. x ray diffraction method • 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. • In an X-ray diffraction measurement, a crystal is mounted on a goniometer and gradually rotated while being bombarded with X-rays, producing a diffraction pattern of regularly spaced spots known as reflections. • It is tedious time consuming so it is not used or unsuitable for routine use. 2/1/2013 22
  • 23. Application:- • many materials can form crystals—such as salts, metals, minerals, semiconductors, as well as various inorganic, organic and biological molecules—X-ray crystallography has been fundamental in the development of many scientific fields 2/1/2013 23
  • 24. 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. • A DTA consists of a sample holder comprising thermocouples, sample containers and a ceramic or metallic block; a furnace; a temperature programmer; and a recording system. • The key feature is the existence of two thermocouples connected to a voltmeter. • One thermocouple is placed in an inert material such as Al2O3, while the other is placed in a sample of the material under study. • As the temperature is increased, there will be a brief deflection of the voltmeter if the sample is undergoing a phase transition. 2/1/2013 24
  • 25. Differential Scanning Calorimetric (DSC) • DSC 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. • Samples that may be studied by DSC or DTA are: Powders, fibers , single crystals, polymer films, semi-solids. • DSC measures endothermic and exothermic transitions as a function of temperature. • –Endothermic heat flows into a sample. • –Exothermic heat flows out of the sample. 2/1/2013 25
  • 26. Differential Scanning Calorimeter (TA Instruments Q10, Q 100,Q 1000) 2/1/2013 26
  • 27. Applications of DTA / DSC in preformulation studies 1. 1. To determine the purity of a sample 2. To determine the number of polymorphs and to determine the ratio of each polymorph 3. To determine the heat of solvation . 4. To determine the thermal degradation of a drug or excipients . 5. To determine the glass-transition temperature(tg) of a polymer. 2/1/2013 27
  • 28. 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 measurements: weight and temperature change. • As many weight loss curves look similar, the weight loss curve may require transformation before results may be interpreted. 2/1/2013 28
  • 29. • 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. • TGA Q 500. 2/1/2013 29
  • 30. Dilatometry • Measure change in volume caused by thermal or chemical effect. • Using dilatometry the melting behaviour of Theobroma Oil was studied. • Extremely accurate but tedious , time consuming and not widely used. 2/1/2013 30
  • 31. Melting point • M.P. determination are often useful technique, but only when substance undergoing investigation heated through phase transition without decomposition. 2/1/2013 31
  • 32. Parameter to checked by preformulator 1. No of polymorphs 2. Relative degree of stability 3. Presence of glassy state 4. Stabilization of metastable form 5. Temperature stability range 6. Solubility of each polymorph 7. Method of preparation 8. Effect of micronization 9. Excipients incompatibility 2/1/2013 32
  • 33. Factor affecting polymorphism A) Temperature and Humidity:- • Storage conditions affect physicochemical reaction which are accelerated at higher temperature. • Humidity acts as a catalyst on the solid surface. • E.g. 1. Zanoterone the solid degradation rate of form 4 is found to be greater than that of form 3 at 40 C/ 25 %RH and 40 C/75% RH. At 40 C/ 25 %RH , the rate of degradation is 4 fold higher for form 4 vs 3. 2. Polymorphic transformation of cocoa butter occur after heating. 2/1/2013 33
  • 34. B) Photostability • Generally light sensitive drug are protected form the photolytic degradation by packing them suitable in light resistant container. • Stable crystalline form resist photochemical degradation and does not require light resistant system. E.g. 1) Acetametacin alpha, beta – stable gamma - unstable. 2/1/2013 34
  • 35. C) Effect of solvent • Solvent can bring dramatic change in growth mechanism and morphology. • Kinetic of crystal growing form solution was determined by two important factors. a. degree of molecular roughness b. nature of absorption of the solvent from surface. 2/1/2013 35
  • 36. D) Effect of grinding • Grinding process reduces particle size, so increasing specific surface area and that why direct effect on dissolution rate and bioavaibility of the formulation. • During process solid state polymorphic transformation in to non crystalline or metastable form is caused by mechanical action. • E.g.- dihydrate form is more stable than anhydrous form. With increasing grinding time compound become unstable because grinding weakened bonding crystals and water molecules. 2/1/2013 36
  • 37. E) Effect of tablet compression:- • Stability and compaction behavior form of of the polymorphic form of drug is important • Phenylbutazone in which form 3 converted to 2 form at >2000kg/cm2. 2/1/2013 37
  • 38. Effect of polymorphism on bioavailability  If the absorption of active ingredient in drug through G.I.T. is dissolution rate dependent then polymorphism is an important preformulation tool.  Here successful utilization of polymorph having significant greater thermodynamic activity (solubility)may provide good therapeutic blood level from otherwise inactive drugs. Eg novobiocin .  two different forms : crystalline and amorphous. In tablet or capsule formulation  novobiocin is used as sodium salt which is active orally but unstable chemically while insoluble form is stable chemically and orally inactive.(unabsorbable ) 2/1/2013 38
  • 39. APPLICATION 1. The knowledge of solid-state properties in an early stage of drug development helps to avoid manufacturing problems, to fine-tune the performance of drugs and provides space for innovations . e.g.- Famotidine which is an excellent histamine H2 receptor antagonist is also found to exist in two different polymorphic forms, metastable polymorph B and stable polymorph A. 2. For improvement of therapeutic activity of drug. 3. To prevent loss of raw material. 4. For better bioavailabity of drug. . 2/1/2013 39
  • 40. Conclusion • Differences in the solubility and melting point must also be assessed and then a decision can be made to determine which form to progress through to the next stage. • Metastable form may lead to a preferential choice of a polymorph other than sable form . • As polymorphism can have such serious consequences for the bioavailability of drugs with low aqueous solubility. 2/1/2013 40
  • 41. Study Question 1. What is polymorphism? Discuss its significance in dissolution. Enumerate the methods to identify polymorphs. 6 mark ( GTU July 2012 ) 2/1/2013 41
  • 42. References 1. The theory and practice of industrial pharmacy by- Leon Lechman , Joseph L Kanig . 2. Biopharmaceutics and pharmacokinetics by- DM Bhramankar , Sunil Jaiswal . 3. Physical pharmacy by- Alfred Martine. 4. The science of dosage form design by Michael E Alton . 5. Encyclopedia of pharmaceutical technology . 2/1/2013 42