crystal morphology & polymorphysm

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Crystal morphology & Polymorphism : 

Dept. of Quality Assurance 1 Crystal morphology & Polymorphism Amit P.Patel 1st yr. M.Pharm Quality Assurance KLES’s college of pharmacy

Contents : 

Dept. of Quality Assurance 2 Contents Definition & Introduction Crystal habit Types Conditions Shapes Polymorphism Techniques References

Crystals : 

Dept. of Quality Assurance 3 Crystals Crystals are characterized by repetition of the constituent atoms in a regular three dimensional structure which is absent in glasses and some polymers and the other state of matter. There are various crystal systems, differing in atom arrangement characterized by the length of three axes and spatial arrangement. Crystal forms play an important role in physicochemical property of drug.

Continued… : 

Dept. of Quality Assurance 4 Continued… Internal structure of a compounds can be classified as 1. Crystalline 2. Amorphous Crystalline materials are those in which the molecules are packed in a defined order, and this same order repeats over and over again throughout the particle. 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.

Crystal habit : 

Dept. of Quality Assurance 5 Crystal habit Crystal habit is description of outer appearance of crystal. Crystal habit & internal structure of drug can affect bulk & physicochemical property of molecule. 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.

Different types of crystal habit : 

Dept. of Quality Assurance 6 Different types of crystal habit

Crystal habit is affected by conditions. : 

Dept. of Quality Assurance 7 Crystal habit is affected by conditions. Supersaturation tends to transform a prism or granule to a needle shape. Cooling rate and agitation is effective in changing habit since it changes the degree of supersaturation.Ex.Naphthalene gives thin plates (platy) if recrystallized in cold ethanol or methanol,whereas slow evaporation yields prisms.

Continued… : 

Dept. of Quality Assurance 8 Continued… The crystallizing solvent affects habit by preferential absorption onto certain faces inhibiting their growth.Ex.Resorcinol produces needles from benzene and squat prisms from butyl acetate. The addition of cosolvents or other solutes and ions may change habit by poisoning crystal growth in one or more direction.Ex.Sodium chloride is usually cubic but urea causes an octahedral habit.

Different shapes of crystals : 

Dept. of Quality Assurance 9 Different shapes of crystals Cubic or isometric - not always cube shaped. Also find as octahedrons (eight faces) and dodecahedrons (10 faces). Tetragonal- similar to cubic crystals, but longer along one axis than the other, forming double pyramids and prisms. Orthorhombic - like tetragonal crystals except not square in cross section (when viewing the crystal on end), forming rhombic prisms or dipyramids (two pyramids stuck together). Hexagonal - six-sided prisms. When you look at the crystal on-end, the cross section is a hexagon. Trigonal - possess a single 3-fold axis of rotation instead of the 6-fold axis of the hexagonal division. Triclinic - usually not symmetrical from one side to the other, which can lead to some fairly strange shapes. Monoclinic - like skewed tetragonal crystals, often forming prisms and double pyramids.

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Dept. of Quality Assurance 10

Slide 11: 

Dept. of Quality Assurance 11 NaCI crystal structure ( - Na, ● - Cl). Hexagonal 2D diatomic lattice composed of atoms (a) of different types (b) of the same type.

Polymorphism : 

Dept. of Quality Assurance 12 Polymorphism It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice. When a substance exists in more than one crystalline form, the different forms are designated as polymorphs and the phenomenon as polymorphism. Polymorphs are of 2 types 1. Enatiotropic 2. Monotropic

Continued… : 

Dept. of Quality Assurance 13 Continued… The polymorph which can be changed from one form into another by varying temp. or pressure is called as Enantiotropic polymorph. Eg. Sulfur. One polymorph which is unstable at all temp. & pressure is called as Monotropic polymorph. Eg. Glyceryl stearate.

Continued… : 

Dept. of Quality Assurance 14 Continued… During preformulation it is important to identify the polymorph that is stable at room temp. High melting point=strong lattice=hard to remove a molecule=low dissolution rate Since the metastable forms have greater aqueous solubility,they show better bioavailability therefore they are preferred in formulation.

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Dept. of Quality Assurance 15 Continued… Eg. 1)Chloromphenicol palmitate exist in A,B & C forms,of these B form is more stable & most preferable. Polymorph differ from each other with respect to their physical property such as Solubility Hardness Melting point Crystal shape Density

Techniques for studies of crystals : 

Dept. of Quality Assurance 16 Techniques for studies of crystals Microscopy Hot stage microscopy Thermal analysis X-ray diffraction

Microscopy : 

Dept. of Quality Assurance 17 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.

Continued… : 

Dept. of Quality Assurance 18 Continued… 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.

Hot stage microscopy : 

Dept. of Quality Assurance 19 Hot stage microscopy The polarizing microscope fitted with hot stage is useful for investigating polymorphism, melting point & transition temp. Disadvantage : In this technique, the organic molecules can degrade during the melting process and recrystallization of the melt may not occur.

Continued… : 

Dept. of Quality Assurance 20 Continued… Results of hot stage microscopy Diagrammatic representation

Thermal analysis : 

Dept. of Quality Assurance 21 Thermal analysis Differential scanning calorimetry (DSC) & Differential thermal analysis (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.

Continued… : 

Dept. of Quality Assurance 22 Continued… For characterizing crystal forms , the heat of fusion can be obtained from the area under DSC for melting endotherms. Similarly, heat of transition from one polymorph to another may be calculated.

Continued… : 

Dept. of Quality Assurance 23 Continued… A sharp symmetric melting endotherm can indicate relative purity of molecule. A broad asymmetric indicates presence of impurities. Disadvantage : Degradation during thermal analysis may provide misleading results.

X-ray diffraction : 

Dept. of Quality Assurance 24 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.

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Dept. of Quality Assurance 25

Continued… : 

Dept. of Quality Assurance 26 Continued… 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.

Continued… : 

Dept. of Quality Assurance 27 Continued… Mixtures of different crystalline forms can be analyzed using normalized intensities at specific angles, which are unique for each crystalline form. 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.

References : 

Dept. of Quality Assurance 28 References The theory and practice of industrial pharmacy-By Leon Lachman. 3rd edition Pharmaceutical preformulation the physiochemical properties of drug substance By James I.wells Biopharmaceutics and pharmacokinetics- By D.M.Brahmankar. Pharmaceutics-The design and manufacture of medicines by Michael E.Aulton.


Dept. of Quality Assurance 29 THANK YOU

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