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PREFORMULATION STUDIES:
PHYSICOCHEMICAL
CHARACTERIZATION OF NEW DRUG
MOLECULES
PRESENTED BY
GLADYSTON NETTO
1ST M.PHARM
DE...
CONTENTS
1 Introduction
2 Major area of preformulation research
a) Organoleptic characters
b) Bulk characterization
c) Sol...
PREFORMULATION
 It is defined as the phase of research and development in
which preformulation studies characterize physi...
OBJECTIVES
 To establish the physico-chemical parameters of a new drug entity
 To determine its kinetics and stability
...
Major Area of Preformulation
Research
 ORGANOLEPTIC CHARACTERS
 BULK CHARACTERS
 Crystallinty and polymorphism
 Hygros...
 Solubilization
 Partition co-efficient
 Dissolution
 STABILITY ANALYSIS
 Stability in toxicology formulations
 Solu...
ORGANOLEPTIC CHARACTERS
 Colour,odour, taste of the new drug must be
recorded
COLOUR ODOUR TASTE
Off-white pungent Aci...
BULK CHARACTERIZATION
Crystallinity
 Crystal habit & internal structure of drug can affect bulk &
physicochemical propert...
Different shapes of crystals
905/12/2015 NGSMIPS
Different shapes of crystals
 Depending on internal structure compounds is classified as
1. Crystalline
2. Amorphous
 Cr...
Polymorphism
 It is the ability of the compound to crystallize as more than one
distinct crystalline species with differe...
 Polymorphs differ from each other with respect to their physical
property such as
• Solubility
• Melting point
• Density...
ANALYTICAL METHODS FOR THE
CHARACTERIZATION OF SOLID FORMS
 Microscopy
 Hot stage microscopy
 Thermal analysis
 X-ray ...
Microscopy
 Material with more than one refractive index are anisotropic & appear
bright with brilliant colors against bl...
Hot stage microscopy
 The polarizing microscope fitted with hot stage is useful for
investigating polymorphism, melting p...
Thermal analysis
 Differential scanning calorimetry (DSC) & Differential thermal analysis
are (DTA) are particularly usef...
X-ray diffraction
 Working :
When beam of nonhomogenous X-ray is allow to pass through the
crystal, X-ray beam is diffrac...
 Random orientation of crystal lattice in the powder causes the
X-ray to scatter in a reproducible pattern of peak intens...
HYGROSCOPICITY
 Many drug substances, particularly water –soluble salt forms, have a
tendency to adsorb atmospheric moist...
Hygroscopicity is tested by:
Samples are exposed to the moisture
exposed to controlled relative humidity environments
mois...
PARTICLE SIZE
 Particle size is characterized using these terms :
 Very coarse, Coarse, Moderately coarse, Fine ,Very
fi...
Methods to Determine Particle Size
 Sieving (5µ-150µ)
 Microscopy(0.2µ-100µ)
 Sedimentation rate method(1µ-200µ)
 Ligh...
POWDER FLOW PROPERTIES
 Powder flow properties can be affected by change in
particle size, shape & density.
 The flow pr...
Determination of Powder Flow Properties
 By determining Angle of Repose.
 A greater angle of repose indicate
poor flow.
...
Methods to determine angle of
repose
 Static angle of
repose
 Fixed-funnel
method
 Fixed-cone method
 Kinetic or dynam...
 Measurement of free flowing powder by
compressibility.
 Also known as Carr's index.
CARR’S INDEX(%) =(TAPPED DENSITY – ...
Carr’s Index Type of flow
5-15 Excellent
12-16 Good
18-21 Fair To Passable
23-35 Poor
33-38 Very Poor
>40 Extremely Poor
D...
SOLUBILITY STUDIES
1. Solution phase equilibrium with solid phase at a stated temperature and
pressure .
2. Determines amo...
 The equilibrium solubility is based on the phase-solubility technique
proposed by Higuchi-Connors .
Method
Drug disperse...
pKa determination
 pKa is the dissociation constant of a drug
 The un-ionized drug is lipid soluble thus permeates throu...
SOLUBILIZATION
“Solubilization is defined as the spontaneous
passage of poorly water soluble solute
molecules into an aque...
 It is the process by which apparent solubility of an otherwise
sparingly soluble substance is increased by the presence ...
 When surfactants are added to the liquid at low concentration they
tend to orient at the air-liquid interface .
 On fur...
 Addition of co-solvent
 pH change method
 Reduction of particle size
 Temperature change method
 Hydotrophy
 Additi...
Partition Coefficient
 A measurement of drug lipophilicity i,e the ability to cross the cell
membrane
Distribution coeffi...
SHAKE FLASK METHOD
 Drug is shaken between octanol and water.
 Aliquot is taken and analyzed for drug content
 RULE OF ...
DISSOLUTION
 When Kd << Ka ,dissolution is significantly slower and the absorption is
described as dissolution-rate limit...
 Constant surface area is obtained by compressing powder into a disc of
known area with a die and punch apparatus.
 Hydr...
STABILITY ANALYSIS
1. Solution stability
2. Solid state stability
SOLUTION STABILITY
 The decomposition of drug occurs th...
Oxidation
 used to evaluate the stability of pharmaceutical preparations
 Eg : steroids, vitamins, antibiotics, epineph...
 Photolysis
pharmaceutical compounds
exposure to uv light
absorbs the radiant energy
undergoes degradative reactions
SOLI...
Solid-State Stability profile of a new compound
 Samples are placed in open vials and are exposed directly to a variety o...
 Mole fraction of the solid that has liquefied (Fm ) is
directly proportional to its decay rate.
-molar heat of fusion
Tm...
Drug- excipient compatibility
 Compatibility test play a very important role in the preformulation
studies of oral dosage...
METHOD
stored at a particular temperature (500 C) and analysed
 In emulsions the studies include measuring the critical m...
05/12/2015 NGSMIPS 46
CONCLUSION
 Preformulation studies on a new drug molecule provide
useful information for subsequent formulation of a
phys...
REFERENCE
 Leon Lachman, Liberman. The theory and practice of
Industrial pharmacy, Edn 4. CBS publishing house, New
Delhi...
4905/12/2015 NGSMIPS
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Preformulation studies

  1. 1. PREFORMULATION STUDIES: PHYSICOCHEMICAL CHARACTERIZATION OF NEW DRUG MOLECULES PRESENTED BY GLADYSTON NETTO 1ST M.PHARM DEPARTMENT OF PHARMACEUTICS 105/12/2015 NGSMIPS
  2. 2. CONTENTS 1 Introduction 2 Major area of preformulation research a) Organoleptic characters b) Bulk characterization c) Solubility characters d) Stability characters 3 Conclusion 4 Reference 05/12/2015 NGSMIPS 2
  3. 3. PREFORMULATION  It is defined as the phase of research and development in which preformulation studies characterize physical and chemical properties of a drug molecule in order to develop safe, effective and stable dosage form. 305/12/2015 NGSMIPS
  4. 4. OBJECTIVES  To establish the physico-chemical parameters of a new drug entity  To determine its kinetics and stability  To establish its compatibility with common excipients  It provides insights into how drug products should be processed and stored to ensure their quality 405/12/2015 NGSMIPS
  5. 5. Major Area of Preformulation Research  ORGANOLEPTIC CHARACTERS  BULK CHARACTERS  Crystallinty and polymorphism  Hygroscopicity  Fine particle characterization  Powder flow properties  SOLUBILITY ANALYSIS  ionization constant-PKa  pH solubility profile  Common ion effect-Ksp  Thermal effects 505/12/2015 NGSMIPS
  6. 6.  Solubilization  Partition co-efficient  Dissolution  STABILITY ANALYSIS  Stability in toxicology formulations  Solution stability  pH rate profile  Solid state stability  Bulk stability  Compatibility 605/12/2015 NGSMIPS
  7. 7. ORGANOLEPTIC CHARACTERS  Colour,odour, taste of the new drug must be recorded COLOUR ODOUR TASTE Off-white pungent Acidic Cream yellow sulphurous Bitter tan Fruity Bland shiny Aromatic Intense Odourless Sweet Tasteless 705/12/2015 NGSMIPS
  8. 8. BULK CHARACTERIZATION Crystallinity  Crystal habit & internal structure of drug can affect bulk & physicochemical property of molecule.  Crystal habit is description of outer appearance of crystal.  Internal structure is molecular arrangement within the solid.  Change with internal structure usually alters crystal habit. Eg. Conversion of sodium salt to its free acid form produce both change in internal structure & crystal habit. 805/12/2015 NGSMIPS
  9. 9. Different shapes of crystals 905/12/2015 NGSMIPS
  10. 10. Different shapes of crystals  Depending on internal structure compounds is classified as 1. Crystalline 2. Amorphous  Crystalline compounds are characterized by repetitious spacing of constituent atom or molecule in three dimensional array.  In amorphous form atom or molecule are randomly placed.  Solubility & dissolution rate are greater for amorphous form than crystalline, as amorphous form has higher thermodynamic energy. Eg. Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption. 1005/12/2015 NGSMIPS
  11. 11. Polymorphism  It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice.  Different crystalline forms are called polymorphs.  Polymorphs are of 2 types 1. Enatiotropic 2. Monotropic  The polymorph which can be changed from one form into another by varying temp or pressure is called as Enantiotropic polymorph. Eg. Sulphur.  One polymorph which is unstable at all temp. & pressure is called as Monotropic polymorph. Eg. Glyceryl stearate. 1105/12/2015 NGSMIPS
  12. 12.  Polymorphs differ from each other with respect to their physical property such as • Solubility • Melting point • Density • Hardness • Compression characteristic Eg. 1)Chloromphenicol exist in A,B & C forms, of these B form is more stable & most preferable. 12 Polymorphism 05/12/2015 NGSMIPS
  13. 13. ANALYTICAL METHODS FOR THE CHARACTERIZATION OF SOLID FORMS  Microscopy  Hot stage microscopy  Thermal analysis  X-ray diffraction  Infrared (IR) spectroscopy  Proton magnetic resonance (PMR)  Nuclear magnetic resonance (NMR)  Scanning electron microscopy (SEM) 1305/12/2015 NGSMIPS
  14. 14. Microscopy  Material with more than one refractive index are anisotropic & appear bright with brilliant colors against black polarized background.  The color intensity depends upon crystal thickness.  Isotropic material have single refractive index and this substance do not transmit light with crossed polarizing filter and appears black.  Advantage : By this method, we can study crystal morphology & difference between polymorphic form.  Disadvantage : This require a well trained optical crystallographer, as there are many possible crystal habit & their appearance at different orientation. 1405/12/2015 NGSMIPS
  15. 15. Hot stage microscopy  The polarizing microscope fitted with hot stage is useful for investigating polymorphism, melting point & transition temp.  Disadvantage : In this technique, the molecules can degrade during the melting process. 1505/12/2015 NGSMIPS
  16. 16. Thermal analysis  Differential scanning calorimetry (DSC) & Differential thermal analysis are (DTA) are particularly useful in the investigation of polymorphism.  It measures the heat loss or gain resulting from physical or chemical changes within a sample as a function of temp.  For characterizing crystal forms , the heat of fusion can be obtained from the area under DSC- curve for melting endotherms.  Similarly, heat of transition from one polymorph to another may be calculated.  A sharp symmetric melting endotherm can indicate relative purity of molecule.  A broad asymmetric curve indicates presence of impurities. 1605/12/2015 NGSMIPS
  17. 17. X-ray diffraction  Working : When beam of nonhomogenous X-ray is allow to pass through the crystal, X-ray beam is diffracted & it is recorded by means of photographic plate.  Diffraction is due to crystal which acts as 3 dimensional diffraction grating toward X-ray. 1705/12/2015 NGSMIPS
  18. 18.  Random orientation of crystal lattice in the powder causes the X-ray to scatter in a reproducible pattern of peak intensities.  The diffraction pattern is characteristic of a specific crystalline lattice for a given compound.  An amorphous form does not produce a pattern mixture of different crystalline forms.  Single – Crystal x-ray provide the most complete information about the solid state. 1805/12/2015 NGSMIPS
  19. 19. HYGROSCOPICITY  Many drug substances, particularly water –soluble salt forms, have a tendency to adsorb atmospheric moisture.  Adsorption and moisture content depend upon the atmospheric humidity, temperature, surface area, exposure and the mechanism of moisture uptake.  The degree of Hygroscopicity is classified into four classes:  Slightly hygroscopic: increase in weight is ≥ 0.2% w/w and < 2% w/w  Hygroscopic : increase in weight is ≥ 0.2 % w/w and < 15 % w/w  Very hygroscopic : increase in weight is ≥ 15% w/w  Deliquescent : sufficient water is adsorbed to form a solution 1905/12/2015 NGSMIPS
  20. 20. Hygroscopicity is tested by: Samples are exposed to the moisture exposed to controlled relative humidity environments moisture uptake is monitored at different time points Analytical methods which is used are :  Gravimetry  Karl Fischer Titration  Gas chromatography 2005/12/2015 NGSMIPS
  21. 21. PARTICLE SIZE  Particle size is characterized using these terms :  Very coarse, Coarse, Moderately coarse, Fine ,Very fine .  Particle size can influence variety of important factors : - Dissolution rate - Suspendability - Uniform distribution - Penetrability - Lack of grittiness 05/12/2015 21NGSMIPS
  22. 22. Methods to Determine Particle Size  Sieving (5µ-150µ)  Microscopy(0.2µ-100µ)  Sedimentation rate method(1µ-200µ)  Light energy diffraction(0.5µ-500µ)  Laser holography(1.4µ-100µ) 2205/12/2015 NGSMIPS
  23. 23. POWDER FLOW PROPERTIES  Powder flow properties can be affected by change in particle size, shape & density.  The flow properties depends upon following- 1. Force of friction. 2. Cohesion between one particle to another.  Fine particle posses poor flow by filling void spaces between larger particles causing packing & densification of particles.  By using glident we can alter the flow properties. e.g. Talc 2305/12/2015 NGSMIPS
  24. 24. Determination of Powder Flow Properties  By determining Angle of Repose.  A greater angle of repose indicate poor flow.  It should be less than 30°. & can be determined by following equation. tan θ = h/r. where, θ = angle of repose. h=height of pile. r= radius. Angle of Repose ( In degree) Type of Flow <25 Excellent 25-30 Good 30-40 Passable >40 Very poor 2405/12/2015 NGSMIPS
  25. 25. Methods to determine angle of repose  Static angle of repose  Fixed-funnel method  Fixed-cone method  Kinetic or dynamic method  Rotating cylinder method  Tilting box method 2505/12/2015 NGSMIPS
  26. 26.  Measurement of free flowing powder by compressibility.  Also known as Carr's index. CARR’S INDEX(%) =(TAPPED DENSITY – POURED DENSITY) X 100 TAPPED DENSITY  It is simple, fast & popular method of predicting powder flow characteristics. Determination of Powder Flow Properties 2605/12/2015 NGSMIPS
  27. 27. Carr’s Index Type of flow 5-15 Excellent 12-16 Good 18-21 Fair To Passable 23-35 Poor 33-38 Very Poor >40 Extremely Poor Determination of Powder Flow Properties 2705/12/2015 NGSMIPS
  28. 28. SOLUBILITY STUDIES 1. Solution phase equilibrium with solid phase at a stated temperature and pressure . 2. Determines amount of drug dissolved , amount of drug available for absorption. 3. Solubility reduction is carried out in certain conditions:  Enhancement of chemical stability.  taste masking products.  Production of sustained release products.  Table: Solubility based classification of drug Descriptive term Parts of solvent required for 1 part of solute Very soluble Less than 1 Freely soluble From 1 to 10 Soluble From 10 to 30 Sparingly soluble From 30 to 100 Slightly soluble From 100 to 1000 Very slightly soluble From 1000 to 10,000 Practically insoluble 10,000 and over 2805/12/2015 NGSMIPS
  29. 29.  The equilibrium solubility is based on the phase-solubility technique proposed by Higuchi-Connors . Method Drug dispersed in solvent in a closed container agitated at a constant temperature using shakers samples of the slurry are withdrawn as a function of time clarified by centrifugation and assayed by HPLC, UV, GC etc 2905/12/2015 NGSMIPS
  30. 30. pKa determination  pKa is the dissociation constant of a drug  The un-ionized drug is lipid soluble thus permeates through lipid membrane.  The ionized substance is lipid insoluble therefore permeation is slow  Degree of ionization depends on pH Henderson-Hasselbalch equation  For basic compounds:  For acidic compounds:  Determined by uv spectroscopy, potentiometric titration, titrimetric method ][ ][ ionizedun ionized pKapH   ][ ][ ionized ionizedun pKapH   101 10 )( )( % pKapH pKapH ionized     3005/12/2015 NGSMIPS
  31. 31. SOLUBILIZATION “Solubilization is defined as the spontaneous passage of poorly water soluble solute molecules into an aqueous solution of a soap or detergent in which a thermodynamically stable solution is formed ”. 3105/12/2015 NGSMIPS
  32. 32.  It is the process by which apparent solubility of an otherwise sparingly soluble substance is increased by the presence of surfactant micelles .  MICELLES: -  The mechanism involves the property of surface active agents to form colloidal aggregates known as micelles . 3205/12/2015 NGSMIPS
  33. 33.  When surfactants are added to the liquid at low concentration they tend to orient at the air-liquid interface .  On further addition of surfactant the interface becomes completely occupied and excess molecules are forced into the bulk of liquid.  At very high concentration surfactant molecules in the bulk of liquid begin to form micelles and this concentration is know as CRITICAL MICELLE CONCENTRATION (CMC) 3305/12/2015 NGSMIPS
  34. 34.  Addition of co-solvent  pH change method  Reduction of particle size  Temperature change method  Hydotrophy  Addition of Surfactant  Dielectrical Constant  Complexation 34 General Method of Increasing the Solubility 05/12/2015 NGSMIPS
  35. 35. Partition Coefficient  A measurement of drug lipophilicity i,e the ability to cross the cell membrane Distribution coefficient  For acids:  For bases :  The octanol-water system is widely accepted to explain these phenomenon.  Buccal membrane : butanol-pentanol system  Blood-Brain barrier: chloroform-cyclohexane  Determined by SHAKE FLASK METHOD c cp aqueous organic ao  / )( 101logloglog )( 101010 pKapH PD   )( 101logloglog 101010 pHpKa PD   3505/12/2015 NGSMIPS
  36. 36. SHAKE FLASK METHOD  Drug is shaken between octanol and water.  Aliquot is taken and analyzed for drug content  RULE OF FIVE : for drug permeates through passive diffusion 1. Log P is greater than 5 2. Molecular weight >500 3. There are more than 5 hydrogen bond donors (number of NH + OH) 4. There are more than 10 hydrogen bond acceptors (number of hydrogen + oxygen ) 5. Molar refractivity should be between 40-130 3605/12/2015 NGSMIPS
  37. 37. DISSOLUTION  When Kd << Ka ,dissolution is significantly slower and the absorption is described as dissolution-rate limited.  The dissolution rate of drug substance in which surface area is constant during dissolution is described by Noyes-Whitney equation. Solid drug in the G.I Fluid Drug in solution in the G.I fluid Drug systemic circulation Kd Ka Rate constant of dissolution Rate constant of absorption )( CCS hV DA dt dC  dC/dt=dissolution rate h=diffusion layer thickness C=solute concentration in bulk solution V=volume of the dissolution medium D=diffusion coefficient A=surface area of the dissolving solid Cs=solute concentration in the diffusion layer 3705/12/2015 NGSMIPS
  38. 38.  Constant surface area is obtained by compressing powder into a disc of known area with a die and punch apparatus.  Hydrodynamic conditions are maintained with Static-disc dissolution apparatus and Rotating disc apparatus  fig : static dissolution apparatus and rotating disc apparatus 3805/12/2015 NGSMIPS
  39. 39. STABILITY ANALYSIS 1. Solution stability 2. Solid state stability SOLUTION STABILITY  The decomposition of drug occurs through hydrolysis, oxidation, photolysis.  Hydrolysis (anaesthetics, vitamins etc ) a) Ester hydrolysis R’-COOR + H+ + OH- RCOOH + ROH ester acid alcohol b) Amide hydrolysis RCONHR’ + H+ + OH- RCOOH + H2N-R’ amide acid amine 3905/12/2015 NGSMIPS
  40. 40. Oxidation  used to evaluate the stability of pharmaceutical preparations  Eg : steroids, vitamins, antibiotics, epinephrine  Autoxidation Materials + molecular oxygen homolytic fission Free radicals are produced.  Oxygen sensitivity is measured by bubbling air through the compound or adding hydrogen peroxide. 4005/12/2015 NGSMIPS
  41. 41.  Photolysis pharmaceutical compounds exposure to uv light absorbs the radiant energy undergoes degradative reactions SOLID-STATE STABILITY  1o objective: identification of stable storage conditions. identification of compatible excipients.  Solid-state stability depends on the temperature , light, humidity, polymorphic changes, oxidation. 4105/12/2015 NGSMIPS
  42. 42. Solid-State Stability profile of a new compound  Samples are placed in open vials and are exposed directly to a variety of temperatures, humidities, and light intensities for up to 12 weeks.  Vials exposed to oxygen and nitrogen to study the surface oxidation and chemical stability , polymorphic changes and discolouration.  Stability data obtained at various humidities may be linearized with respect to moisture using the following apparent decay rate constant (KH ) gpl= concentration of water in atmosphere in units of grams of water per liter of dry air . ko = decay rate constant at zero relative humidity kk gplH 0 ].[ 4205/12/2015 NGSMIPS
  43. 43.  Mole fraction of the solid that has liquefied (Fm ) is directly proportional to its decay rate. -molar heat of fusion Tm - absolute melting point T - absolute temperature R - gas constant ][lnln 11 TT H Fk m fus mapp R    H fus  4305/12/2015 NGSMIPS
  44. 44. Drug- excipient compatibility  Compatibility test play a very important role in the preformulation studies of oral dosage forms  An incompatibility in the dosage form can result in any of the following changes:  Changes in organoleptic properties  Changes in dissolution performance  Physical form conversion  An decrease in potency 4405/12/2015 NGSMIPS
  45. 45. METHOD stored at a particular temperature (500 C) and analysed  In emulsions the studies include measuring the critical micelle concentration of the formulations  For oral use preparations compatibility of the ingredients (ethanol, glycerine, syrup, sucrose, buffers and preservatives) Drug + Excipients (1:1) Powder samples dispersed into glass ampoules 1 ampoule 1 ampoule (sample + water) 4505/12/2015 NGSMIPS
  46. 46. 05/12/2015 NGSMIPS 46
  47. 47. CONCLUSION  Preformulation studies on a new drug molecule provide useful information for subsequent formulation of a physicochemically stable and biopharmaceutically suitable dosage form.  Preformulation work is the foundation of developing efficacious and economical formulations. 4705/12/2015 NGSMIPS
  48. 48. REFERENCE  Leon Lachman, Liberman. The theory and practice of Industrial pharmacy, Edn 4. CBS publishing house, New Delhi.2013 p:217-307.  Banker GS, Rhodes CT. Modern pharmaceutics, Edn 4. Marcel Dekker, New York. 2002 p:167-184.  Loyd V. Allen, Nicholas G.popovich, Howard C. Ansel. Ansel’s pharmaceutical Dosage forms & Drug delivery systems, Edn 8. B.I.Publication pvt. Ltd, p:187-193,42 & 43,126-133.  Brahmankar D.M, Jaiswal BS. Biopharmaceutics and pharmacokinetics a Treatise, Edn 2. Vallabh Prakashan, Nagpur. 2009; p: 37-45. 05/12/2015 NGSMIPS 48
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