PHYSICOCHEMICAL PROPERTIES OF DRUG MOLECULES

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PHYSICOCHEMICAL PROPERTIES OF DRUG MOLECULES

• By
• Dr. S. Adebayo

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Polymorphism

• A function of internal arrangement/structure of
  crystalline solids
• Polymorphic substances exist in more than one
  packing arrangement

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• McCrones Law states that every compound has
  different polymorphic forms, and that, in
  general,the number of forms known for a given
  compound is proportional to the time and money
  spent in research on that compound.

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Polymorphism

• Occurrence of more than one morphic form
• Monotropic
• Enantiotropic
• Amorphism

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Crystal habit

• The outward appearance of a crystal
• Independent of morphic forms
• Can be defined on the basis of variations on the
  themes of 7 systems
• Cubic, tetragonal, orthorhombic, monoclinic,
  riclinic, trigonal, hexagonal

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Angles lengths that describe crystal habits
Crystal Angle of axes Length of axes Examples
Cubic (regular) a ß ? 90º x y z NaCl
Tetragonal a ß ? 90º x y ?z NiSO4
Orthorhombic a ß ? 90º x ?y ?z K2MNO4
Monoclinic a ß ? ? 90º x ?y ?z Sucrose
Triclinic (asymmetric) a ?ß ? ? ? 90º x ?y ?z CuSO4
Trigonal (rhombohedral) a ß ? ?90º x y z NaNO3
Hexagonal Z at 90º to base - AgNO3

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Vector illustration of Angles and lengths of axes
that describe crystal habits
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Crystal Systems
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Crystal Morphology Habit
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Monoclinic
simple monoclinic centered monoclinic

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Rhombohedral
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Tetragonal (Wulfenite)
simple tetragonal body-centeredtetragonal

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Tetragonal
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Orthorhombic xtals
simple orthorhombic base-centeredorthorhombic body-centeredorthorhombic face-centeredorthorhombic
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Orthorhombic (Danburite)
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Granular e.g. Tungstate (CaWO4)
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Acicular
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Monoclinic (Realgar)
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Hexahedral (Vanadinite)
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SEM OF BREADFRUIT CORN STARCH POWDERS (Adebayo
Itiola, 2005 2008)
Thursday, May 14, 2020
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Scanning Electron micrographs of (A) Bitter yam,
(B) Chinese yam, (C) Round leaf yellow yam, (D)
Sweet yam and (E) Negro yam (Riley, Adebayo et al
(2008)
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Crystal habit and drug properties

• Changes in crystal habit can influence
• dissolution rate,
• powder flow
• compressibility.

• can have significant effect on processability and
  use of dosage forms.

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Crystal habit and drug properties

• Effect on dissolution rate can be explained by
  the changes in surface to volume ratio
• Transition from regular to acicular (needle)
  shape crystals (e.g. aspirin) may be reflected as
  poor flow property.

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Origin of Crystal Habit

• Habit is determined by the rate of growth of
  different faces of a crystal.
• Hence, it can be altered by changes in
  crystallization process.
• Generally, the fastest growing faces tend to grow
  out of existence
• Will be the smallest faces on the final crystal
• the slowest growing faces will dominate the final
  structure.

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Origin of Crystal Habit

• Solvent of crystallization
• crystallizing solvent may preferentially favour
  interaction with different faces and consequently
  alter the crystal habit.

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Origin/changes in crystal habit

• The presence of impurities - may be caused by
• impurities
• breakdown products
• synthetic precursors in the crystallization
  mixture
• a deliberate addition of impurities (e.g. SAAs)

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Crystal Defects

• Imperfections due to point defects or
  dislocations during packing of lattice
• Due to addition or accidental presence of low
  conc. of impurities
• Can cause major changes in
• Ease of processing
• Chemical reactivity
• Dissolution
• Bioavailability

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Obtaining the right habit

• The preformulation scientist should consider the
  optimum form of habit
• Possibly influence crystallization procedures to
  ensure optimum properties are not serendipitous
  but rather a result of crystal engineering.

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Characterization of crystal habits

• Crystal habit morphology can best be studied by
  microscopic techniques.
• Standard light microscopes fitted with polarizing
  filters and phase contrast facilities can allow
  easy examination of crystals and quantification
  of habit and size.

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Characterization of crystal habits

• Studies on crystal properties generally involve
  standard tests such as
• melting point to indicate crystal purity and
  crystal form
• thermal analysis.
• Crystal habit can be deduced from
  photomicrography
• For photomicrography, image may be enhanced by
  using polarized light.
• Scanning electron micrography.

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Optical isomers

• Preferred isomer should be identified
• Any other isomers are regarded as impurities
• Column based systems now available for
  determination

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Setting acceptance criteria for drug substance
drug products
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Concepts/Terminologies Relating to Crystalline
Phenomenon Familiarize yourself with them

• Rate of crystallization
• Polymorphism"
• Rate of transition
• Crystal habit
• Crystal growth
• Crystal morphology
• Crystal structure determination
• Interplanar spacing
• Association in the solid state
• Solid state structure properties

• Melting pressure
• Freezing point
• Glass transition temperature
• Phase diagram
• Long spacing
• Reorientation in the solid state
• Spin polarization
• Nuclear spin conversion
• Structure of the solid
• Dimensions of the unit cell

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Polymorphism in pharmaceuticals

• Polymorphism is important in the development of
  pharmaceutical ingredients.
• Many drugs are regulatory approved based on a
  single crystal form or polymorph.

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Crystal Properties and Solubility

• Majority of substances are crystalline in nature
  their molecules are packed in an ordered and
  reproducible manner.
• Excipients also vary from crystalline material to
  armophous polymers.
• Very few samples are, however, entirely
  homogenous
• drugs will at least be partially armophous
• polymers will be partially crystalline.
• The extent of crystallinity will affect their
  physical properties to a significant extent.

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Polymorphism and Solubility

• BP 2001 defines polymorphism as the occurrence of
  more than one morphic forms.
• It is a function of the internal
  arrangement/structure of crystalline solids.
• A polymorphic substance therefore exists in more
  than one packing arrangement.

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Types of polymorphism

• Two types of polymorphism have been identified
• Monotropic polymorphism Those for which only
  one form is stable, irrespective of temperature
  and pressure and the metastable form would revert
  to the stable form with time.
• Enatiotropic polymorphism Different forms are
  stable under different external conditions
• change in temperature and pressure determine the
  form that is stable (Lund, 1994).

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Monotropic polymorphs

• Different monotropic polymorphs
• often have different melting points with the most
  stable form having the highest melting point.
• They also exhibit different x-ray diffraction
  patterns and IR spectra and dissolution rate.
• In some cases, these differences in properties
  may affect the
• handling characteristics of the material,
• the stability of formulated preparations
• bioavailability.

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Occurence

• Occurrence of polymorphism can not be predicted
  because it can be induced in many materials at
  appropriate conditions.
• Moreover, its absence is difficult to demonstrate
  by a single specific test.
• The metastable forms usually have
• faster dissolution rate
• apparently greater equilibrium solubility
• considerably greater bioavailability.

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Polymorphic transition

• Metastable form is not stable and will revert to
  the stable form.
• Transition in polymorphic form can be gradual and
  time-dependent and can be accelerated by increase
  in temperature, humidity or energetic treatment
  as in processing of powder.
• Therefore, unit processes such as mixing, milling
  and tabletting can induce changes in crystal type
  and, hence, change the physical and potential
  biopharmaceutical properties of the drug.

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Need for control of morphic forms

• Necessary during processing of
• active ingredients
• excipients
• during production of formulated products
• to ensure the correct physical and
  biopharmaceutical characteristics of the product.

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Control of morphic forms ..

• Great care is needed to determine
• which polymorph is present,
• under what condition
• how long it will be stable.
• A useful stress test for a drug substance is to
  
• ball-mill it for a defined time
• check for any change in polymorphic form through
  DSC analysis.

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Armophism

• Like polymorphism, transition from armophous to
  crystalline forms and vice versa may have
  significant effect on dissolution.
• Solubility of armophous drugs can be higher than
  that of crystalline form by a factor of 10s or
  100s.
• Hancock Parkes (2000) Pharm. Res. 17 397
  404

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Pseudopolymorphism

• Caused by changes in crystallization process
  which results in inclusion of solvent molecules
  in the crystal thereby producing solvates or
  hydrates.
• The crystals differ in properties from the
  non-solvated sample just like the different
  polymorphic forms.
• referred to as Pseudopolymorphs
• Different solvates of the same drug can produce
  different blood concentrations from administered
  solid oral dosage form.
• Unlike polymorphs in which morphic forms with the
  lowest melting point usually produce the highest
  blood concentration,
• solvates or anhydrous forms may produce higher
  concentrations depending on the particular drug.

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Types of Polymorphism

• Packing polymorphism - polymorphism existing as a
  result of difference in crystal packing
• An example of an organic polymorph is glycine
  which is able to form monoclinic and hexagonal
  crystals.
• Conformational polymorphism - Polymorphism
  resulting from the existence of different
  conformers of the same molecule
• Pseudopolymorphism - the different crystal types
  are the result of hydration or solvation.

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Polymorphism in pharmaceuticals Case Studies

• GlaxoSmithKline defended its patent for the
  polymorph type II of Ranitidine (Zantac).
• For Medicine administered orally as a crystalline
  solid, dissolution rates depend on the exact
  crystal form of a polymorph.

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Polymorphism in pharmaceuticals .

• Polymorphism is not always well understood.
• In 2006 a new crystal form was discovered of
  maleic acid 124 years after the first crystal
  structure determination
• Maleic acid is a chemical manufactured on a very
  large scale in the chemical industry and is a
  salt forming component of drug molecules.

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Polymorphism in pharmaceuticals .

• The new crystal type is produced when a caffeine
  - maleic acid co-crystal (21) is dissolved in
  chloroform and the solvent is allowed to
  evaporate slowly.
• Both polymorphs consist of sheets of molecules
  connected through hydrogen bonding of the
  carboxylic acid groups
• in form I the sheets alternate with respect of
  the net dipole moment
• in form II the sheets are oriented in the same
  direction.

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Polymorphism in pharmaceuticals .

• Polymorphism is also established for aspirin
• A new crystal type was found following attempt to
  co-crystallization of aspirin and levetiracetam
  from hot acetonitrile.
• Form II is only stable at 100 K and reverts to
  from I at ambient temperature.

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Polymorphism in pharmaceuticals .

• In form I two salicyl molecules form
  centrosymmetric dimers through the acetyl groups
  with the (acidic) methyl proton to carbonyl
  hydrogen bonds
• In the newly discovered form II each salicyl
  molecule forms the same hydrogen bonds but then
  with two neighboring molecules instead of one.

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Polymorphism in pharmaceuticals .

• With respect to the hydrogen bonds formed by the
  carboxylic acid groups both polymorphs form
  identical dimer structures.

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Disappearing Crystal Crystal Polymorphs

• The drug Paroxetine was subject to a law suit
  that hinged on such a pair of identical polymorphs

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References

• Florence, A. T. Attwood, D. Physicochemical
  principles of pharmacy, PhP London, 2006
• Investigating the latent polymorphism of maleic
  acid Graeme M. Day, Andrew V. Trask, W. D. Samuel
  Motherwell and William Jones Chemical
  Communications, 2006, (1), 54 - 56 DOI
  10.1039/b513442k
• ?  The Predictably Elusive Form II of Aspirin
  Peddy Vishweshwar, Jennifer A. McMahon, Mark
  Oliveira, Matthew L. Peterson, and Michael J.
  Zaworotko J. Am. Chem. Soc. 2005 127(48) pp
  16802 - 16803 (Communication) DOI
  10.1021/ja056455b

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Physicochemical Properties of Drug Molecules
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