Relevance of Solid Forms in Pharmaceuticals

Palash Sanphui
Process Research,
Lupin Limited

Outline of the talk

Solid state and crystal lattices
Crystallization phenomenon
Types of solid forms
Allotropes and Polymorphs
Amorphous solids
Conclusions

Solid state

Crystalline
(Long range
order)

Meso phase
(Liquid crystals)

Amorphous
(Short range order)

Decreases periodicity
Decreases stability

Crystal lattice
Crystals are periodic arrangement of molecules in the solid state.
Crystalline solids provide stability and utmost purity of a compound.
Seven Crystal lattices

Prism
crystals

Contd.

Lattices>>> The simplest regular array is a line of evenly spaced objects

A one-dimensional lattice (a,b) and the choice of unit cells (c).

The line of dots is called the lattice, and each lattice point (dot) must have identical
surroundings.

Different unit cells

in square 2D lattice

Unit Cell>>> Repeating unit in a crystal lattice

Forces responsible
Interaction

Energy ( KJ/mol)

Covalent interaction

250

Hydrogen bonds

10-40

Dipole dipole interactions

3-5

Van Der Waals interactions

Hydrophobic interactions

<1

H bonding in water

Polar-dipolar interaction
between cation and anion

Molecules in periodic arrt.

Van Der Waal forces

( stacking)

Hydrogen bonds ----most important because of its strength and directionality

Crystallization of a compound
Solubility check in ordinary
solvents, followed by
crystallizations.

Favor stable form

Favor metastable form

Solvent anti-solvent
crystallizations.
Variations of crystallization
conditions (heat, pressure,
cool etc.).
Melt-sublimation.
Grinding of amorphous
form.
Use of spray drier,
lyophilizer, agitated thin
film drier.
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Solvent for crystallizations

Solvent Properties
Hydrogen bond donation ability
Hydrogen bond acceptance ability.
Polarity / Polarizability parameter.
Solvent could be pure or mixture
of solvents.

H bond acceptor
H bond donor

USP Class 3 Residual Solvents List

Acetic acid
Heptane
Acetone
Isobutyl acetate
Anisole
Isopropyl acetate
1-Butanol
Methyl acetate
2-Butanol
3-Methyl-1-butanol
Butyl acetate
Methylethylketone
tert-Butylmethyl ether Methylisobutylketone
Cumene
2-Methyl-l-propanol
Dimethyl sulfoxide
Pentane
Ethanol
1-Pentanol
Ethyl acetate
1-Propanol
Ethyl ether
2-Propanol
Ethyl formate
Propyl acetate
Formic acid

Crystallization from class 3 solvents are preferred because of low toxicity.

Crystallizations from class 2/1 solvents are generally avoided.

8

Crystallization phenomena
Crystallization depends upon the solubility in a certain solvent.
Temperature and entropy of fusion directly effects the solubility.

Controlling process parameters is very important to crystallize a form selectively.

9
Contd.

In a saturated solution, the solute in solution is in eqm with solid solute i.e.
chemical potential is same for the solute in both the phases
Solid + Solvent

Solution

dG = d(HTS)
dG=VdP-SdT

G
d i (
)
ni T, P, nj remaining constant
ast
t
e
M

qm.
e
e
abl

At eqm,
Conc.

ile
Lab

G=0 &

Stable

Temp.

solid=Sol

10

Supersaturation and nucleation

Supersaturation created through
(a) Evaporation
(b) Cooling
(c) pH adjustment
(d) Addition of another solvent having
less solvency power.
Nucleation is the process of forming a nucleus. It is the initial process in crystallization.

Nucleation
Primary
Homogeneous

Secondary
(Induced by crystals)
Heterogeneous

(Induced by foreign particles)

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Effect of supersaturation and crystal size

Anti-solvent added to the solution

Supersaturation is low

Solution added to the Anti-solvent

Supersaturation is high

Tungs et al. Cryst. Growth Des. 2013, 17, 445.

12

Nucleation
Cluster I
or
Aggregate I
Cluster II
or
Aggregate II
or
Embryo II
(about 700-800
molecules

Nucleation is a cluster of few tens of molecules

held together by weak intermolecular forces and
packed in a regular way.
Rate of Nucleation: rate at which clusters grow
through the critical size and become crystals.

Crystal
growth I

Nucleus I

Nucleus II

Nucleation Rate

Molecules
In supersaturated
state, attractive forces
like H-bonding etc.
start operating

Crystal
growth II

Polymorph I

Polymorph II

Rate=Kj eBj 3/T3 2

Rate of Nucleation depends on degree of super

saturation (), temperature (T), bulk & surface
free energy () and solubility (pre-exp factor).

Supersaturation
critical

13

Secondary Nucleation

Seed crystals of NaOAc

Nucleation of new crystals in presence of

crystals or seeds.
Sometimes for crystallization to occur, a
seed crystal must be introduced and the
crystallization process is quite fast.
By seeding one can control the morphology
and also the desired form.
Ostwald rule of stages
A crystallizing system progresses from
the supersaturated system to eqm in
Stage and each stage representing the
smallest possible change in free energy.
Finally most stable phase of lowest free
energy will appear.
14

Various solid forms

Polymorphs are possible for all the above mentioned solid forms.

15

Allotropes

ight allotropes of carbon

a) Diamond
b) Graphite
c) Lonsdaleite

d) C60 (Buckminsterfullerene
or buckyball)
e) C540,
f) C70

A single
layercarbon
of graphite, graphene displays extraordinary
g)
Amorphous
electrical,
thermal, and physical properties.
h)
Carbon nanotube

16

Polymorphs
Polymorphs are different crystalline forms of the same
compound in which molecules have different
arrangements and/or different molecular conformation.
Every compound can be polymorphic if sufficient time
and energy spent.
Display different physical properties such as unit
packing, thermodynamic, spectroscopic, interfacial, and
mechanical properties.

Physical properties: Molar volume & density

Melting and sublimation temperatures
Enthalpy
Solubility, dissolution rate.
Hardness, compactibility
Handling, flow, and blending

McCrone, W. C. Polymorphism. In Physics and Chemistry of the Organic Solid State, 1965

17

Polymorph history and serendipity

Polymorphism in arsenates and phosphates---Mitscherlich (1822)
Polymorphic organic compound---Benzamide by Liebig and Whler (1832)

Few examples of molecules discovered as polymorphs after a long time

1832 (I), 2005 (II)

1881 (I), 2005 (II)

1964 (I), II (2007)

(173 yrs)

(124 yrs)

(43 yrs)

1981 (I), 2011 (II, III)

(30 yrs)

The number of forms known for a given compound is proportional to the time
and money spent in research on that compound-Walter C. McCrone (1965)
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Synthon polymorphs

A: Thermodynamic;
B and C: Kinetic

Form I (A)

Form II (C)

Ravikumar et al. Mol. Cryst. Liq. Cryst., 2009, 515, 190,

Mahapatra et al., Cryst. Growth Des., 2010, 10, 3191 19

Conformational polymorphs
Poor aqueous solubility
(8.7 mg/L).

CURCUMIN
ISOLATION
1842
SYNTHESIS
1918

OH

Form 1 (Z'=1),
Commercial

Form 2 (Z'=2),
New

OH

OH

HO
OMe

CRYSTAL
STRUCTURE
1982

Curcumin

OMe

OH
O2N
HO

N
N

POLYMORPHS
2011

Amorphous
New

Form 3 (Z'=1),
New

Metastable forms dissolve 2-3 times faster than the stable form

Sanphui et al. Chem. Commun. 2011, 47, 5013

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Tautomeric polymorphs
Triclabendazole

Omeprazole

Form I

Form II

5'-methoxy tautomer in form V

Bhatt et. al, Chem. Commun. 2007, 2057.

Tothadi et al., Chem. Asian J., 2012, 7, 330

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Importance of Polymorphism
Polymorphism has great importance in the pharmaceutical industry
because of process development and IP issues
* Novelty * Non-obviousness *Utility
Example 1>>

Paracetamol, analgesic and antipyretic drug

Form I (stable)
Herringbone structure

Form II (metastable)
Layered structure
Suitable for tableting

Form I requires maize starch binder for marketing as tablet formulation.

Perlovich et al. J. Therm. Anal & Cal., 2007, 89, 767

Alternative???

22

Example 2>>
Mebendazole, anthelmintic drug
Form A, most stable
Form B, metastable, toxic
Form C, metastable
Solubility order of three polymorphs in 0.3 (M) HCl, Form B>Form C>Form A.
Polymorph C is therapeutically favored, but tendency to convert to Form A
Eur J Pharm & Biopharm 2003, 55, 345.

Any solution????
Stabilization of form C??
Cocrystals??
23

Example 3>>

Chocolate polymorphs

A key ingredient of chocolate is

cocoa butter.
Cocoa butter exists as
hexamorphs with variation in its
m.p.
Form V has a far superior taste
and texture compared to others.
Stabilizing chocolate is difficult
because of its low m.p.
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Ritonavir. A Disappearing Polymorph?

Form I (1st)

Form II (2nd)

Solubility

Stable form II is 5 times less soluble than form I

Abbott laboratory $ 250 million loss

Bauer et al. Pharm. Res., 2001, 18, 859

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 High throughput screening of a drug is required before launching in the market

Most stable solid form should be preferred in the formulation

26

Recent examples of API polymorphs

Sulfathiazole

Pentobarbital

Paracetamol

Fluconazole

Barbital

Metaxalone

Theophylline

Perindopril Erbumin

Indomethacin

Gabapentin

Aripiprazole

Ranitidine Hydrochloride

Huperzine A

Paracetamol

Irbesartan

Acemetacin

Nalidixic Acid

Felodipine

Pridopidine Hydrochloride

Etoricoxib

Acedapsone

D-Mannitol

L-Citrulline

Prasugrel hydrochloride
Source: Articles in CGD and CEC in 2012-14

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New techniques of polymorph crystallization

Rotavapor technique

Bag et al. Cryst.Growth Des., 2012, 12, 2740

Polymer induced
heteronucleation

Lopez-Mejas et al. J. Am. Chem. Soc., 2009, 131, 4554

Gel induced ROY polymorphs

Diao et al. J. Am. Chem. Soc., 2012, 134, 673

Epitaxial growth

Arlin et al. Chem. Commun., 2011, 47, 28

7074

Highly polymorphic compounds

Decamorphs

Nanomorphs

Chen et al. J. Am. Chem. Soc. 2005, 127, 17439

Mejas et al. J. Am. Chem. Soc. 2012, 134, 9872

Flexible molecules are more prone to form multiple polymorphs

Drug molecules (50%) are more prone to be polymorphic than organic compounds (5%)
29

Stability of polymorphs
Thermodynamics provides the direction and driving force of transformations that
yield the desired form (but not the rate).
The stability of a polymorph is determined by G = H - TS, not just H or S.
H = enthalpy energy
S = entropy
G determines the stability of a phase at constant pressure
The relative stability of two polymorphs depends on their enthalpy and entropy
difference
Energy-entropy compensation is important.

30

Stability relationship (thermal)

Monotropic

Enantiotropic

Phase transformation before melting

No phase transformation till melting
Stability order: Form delta> Form alpha (high T)
Stability order: Form I>Form II
Stability order: Form delta< Form alpha (low T)
Greater H, greater stability.
Greater H, less stability.

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Monotropic relationship

Enantiotropic relationship

At low conc: Form II I--III

Forms I & IImonotropic

At high conc: Form III--II--I

Form I & III---enantiotropic

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Knowledge of solubility is needed to identify the feasible path for crystallization

Solvent Mediated Polymorph transformations

Dissolution
Metastable form

Nucleation
Solution
Crystal growth

&

Stable form

Uric acid
(UA)
Solution-mediated phase transformation of metastable Uric a dihyd to UA
Presores et al. CrystEngComm, 2014,16, 7278

33

Concomitant Polymorphs
Occurance of more than one polymorph from crystallization under
identical condition.
As per phase rule, maximum of three polymorphs can remain in
equilibrium, otherwise F, degree of freedom would be ve.
F=CP+2
C=No. of component, P=phase. Fmin=0

E between the concomitant

polymorphs is 1-2 Kcal/mol

Trimorphs (concomitant) of 6-chloro-2,4-dinitroaniline from DCM

Reddy et al. Chem. Commun., 2005, 2439

34

Characterization of polymorphs

PXRD
Single crystal X-ray diffraction
Differential scanning calorimetry (DSC)
Infrared absorption
Raman spectroscopy
Solid state NMR
Electron microscope (SEM, TEM etc.)

35

Single crystal X-ray diffraction

Crystal

Crystal structure

SCXRD

36

Diffraction spots collected in detector

Powder X-ray diffraction

Purity check

Indexing

Crystal structure

37

Micron size particles are required so that proper orientation of diffraction peaks are possible.

Unit cells of Paracetamol polymorphs

Form I, Monoclinic

Form II, Orthorhombic

Packing differences between two polymorphs

38

IR difference in Ranitidine HCl polymorphs

Impurity of form II in form I was monitored in 1054 cm1

39

Raman spectra confirms the similarity between generic and Form I

40

SSNMR and polymorphs

Conformational difference in Curcumin polymorphs reflects in SSNMR.

Sanphui et al. Chem. Commun., 2011, 47, 5013

41

SEM images of the Norfloxacin polymorphs

Form A

CH3CN

SEM instrument
2-PrOH

Acetone
Form C

Form B
Note, different morphologies of the polymorphs

Barbas et al. J. Therm. Anal. Cal., 2007, 89,687

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Amorphous form
Many pharmaceutical solids exist in amorphous
forms.
Because of high E, amorphous form sometimes
preferred than crystalline stable form in case of
poor solubility issue.
Amorphous forms are less stable and prone to
crystallize under ext. conditions such as heat,
moisture, pressure etc.

Amorphous structure
(Short range order)

Amorphous form can be stabilized by excipients

(increasing Tg) via Solid dispersion, melt etc.

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Why amorphous form?

Amorphous materials generally exhibit higher
dissolution rate than crystalline forms.

Ritanovir
0.1 N HCl at 37C

Law et al. J. Pharm. Sci. 2004, 93, 563

44

Amorphous form preparations

Vapor condensation
Supercooling of liquid
Precipitation from solution
Disruption of crystalline lattice

Solvent evaporation
Freeze drying
Spray drying
Wet granulation
Drying
Grinding
Desolvation
Compaction

Hancock et al. J Pharm. Sci. 1997, 86, 1.

45

Instruments used to prepare amorphous phase

Rotor vapor

Lyophilizer

Spray drier

Melt extrusion

46

PXRD characterizations

Crystalline

Amorphous

PXRD clearly distinguishes between a crystalline and an amorphous material.

47

UV spectrophotometer

UV light basically excite the ground state electrons and when

the excited electron releases energy results fluorescence and
phosphorescence.

48

Fundamental of Molecular Spectroscopy by Banwell & McCash

FT-IR spectrophotometer
A molecule should have change in dipole moment
to be effective in IR spectram.
Asymmetric vibrational modes (C=O, C=N, N-H,
OH, SO2) are effective .
IR spectroscopy is useful for functional groups
identifications.

49

NMR spectroscopy
1. NMR exploits the magnetic properties of certain atomic nuclei ( 1H, 13C, 15N) possessing spin.
2. NMR provide detailed information about the structure, chemical environment of molecules.
3. The multiplicity of a multiplet is given by the number of equivalent protons in neighbouring
atoms plus one, i.e. the (n + 1) rule

Splitting (1:2:1)

Splitting (1:3:3:1)

Splitting of signals
1

H NMR spectrum
CH3CH2OH

50

51

13

C NMR spectrum

H NMR spectrum

Scanning Electron Microscope (SEM) images

SEM provides the m, nm size particles morphology. Nano
particles are useful to improve solubility of drugs .
Electron microscope produces images of a sample by scanning
it with a focused beam of electrons. The electrons interact with
atoms in the sample, producing various signals that can be
detected >>>> samples surface topography and composition.

1 m

218 nm-1.4 m

20 -100 m

Generally block or plate crystals have more surface area and hence better solvent-solute
interactions during dissolution. Hence block morphology crystals will have higher solubility
than their needle counterparts.
52

Thermal analysis (DSC/TGA)

DSC can measure exact m.p., phase transformation, decomposition of the solid phases.
TGA can measure (%) weight loss due to present of water/solvent in the crystal lattice.
From weight loss one can calculate stoichiometry of the solid phase in solvate or hydrate.

Metler Toledo DSC

DSC and TGA of a tertrahydrate sample
DTA can measure temperature differences precisely, but DSC can measure enthalpy accurately
53

Thermal analysis (DSC)

Recrystallization

Super cooled liq

glass
Melting

Hancock et al. J. Pharm. Sci. 1997, 86, 1

54

Glass Transition Temperature

Tg is roughly (0.67)Tm(the melting temperature of the crystalline
material
2/3 rule
Sample
Tg (K) Tm (K) Tg/Tm
Poly(ethylene terephthalate) 343 538 0.64
Nylon 66
333
538 0.61
Polyacrylonitrile
378
590 0.64
Isotacticpolypropylene 268
435 0.62
Aspririn
243
408 0.60
Indomethacin
315
434 0.73
Sodiumindomethacin 393
543 0.72
Nifedipine
323
447 0.72
Cholocalciferol
293
352 0.84

55

Different grades of poly(vinylpyrrolidone) (PVP)

Sample
Molecular Weight (g/mol) Tg(C)
PVP K90
1500 K
177
PVP K30
50K
156
PVP K17
10K
136
PVP K12
2K
101
PVP/VA (60:40)
50K
102

PVP

PVP/VA

Tg of a material can be varied by using PVP via solid dispersion techniques.

High Tg polymers can increase the wettability and hydrophilicity and maintain the molecules in
56
the disordered state for a long time.

Nifedipine case study

Physical Stability
1:4 Nifedipine:PVP amorphous dispersions compressed into tablets
Stored at 60C/75% RH
Dissolution measured in 900 mL of water with 0.1% surfactant at 37C

Crystallinity increases

Slow down in dissolution due to crystallization of nifedipine during storage

Dissolution

Initial
7d
14 d
Nifedipine +
starch

Crystallinity increases>>> rate of dissolution decreases.

57

Solid dispersion
Dispersion of a drug in a solid matrix (e.g. polymer).
The drug and the polymer act as solute and solvent.

Solid
dispersion
method

High dissolution
High stability

Ali et al. Am. Pharmaceutical Rev. 2012

Contd.

58

 When a drug melting event is absent and only one Tg is observed, the solid
dispersion is usually assumed to be a homogeneous.

FDA-approved medicines that use solid dispersion

PVP-Polyvinylpyrrolidone, VA-Vinyl acetate, HPMC-Hydroxypropylmethylcellulose, HPMCAS-Hydroxypropyl

methyl cellulose acetate succinate.

These polymers maintain a supersaturated drug concentration in vivo for an extended

period to allow optimal absorption.
Huang et al. Acta Pharmaceutica Sinica B 2014, 4, 18

59

Amorphous Products
Amorphous active pharmaceutical ingredients (APIs)
marketed as drug products:
Accolate (zafirlukast)
Ceftin (cefuroxime axetil)
Accupril (quinapril hydrochloride)
Viracept (nelfinavir mesylate)
Amorphous solid dispersions marketed as drug
products:
Cesamet (nabilone)
Gris-PEG(griseofulvin)
Isoptin(verapamil)
Kaletra(lopinavir/ritonavir)
Sporanox (itraconazole)
Rezulin (troglitazone)

60

Conclusions
Controlling polymorph via crystallization is a great challenge for pharma industry.
Seeding is an important method of crystallization to obtain desired solid form.
Polymorphs prediction for the flexible molecules is a challenging.
Crystal structure determination is final proof in case of close PXRD patterns.
The polymorphs have to be well characterized by PXRD, DSC, SSNMR, IR etc.
Phase transitions for the enantiotropic polymorphs have to be taken care of.
Marketing of most stable form is essential to avoid phase transformation post launch.
Stabilization of amorphous form via solid dispersion is becoming popular.

61

Acknowledgements
Dr. B. N. Roy
Dr. G. P. Singh
Dr. Nandu Bhise
Lupin Ltd.

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