The document discusses the use of metastable polymorphs to enhance oral bioavailability. It begins by defining polymorphism as the ability of a compound to crystallize in more than one distinct crystal structure. Metastable polymorphs are excited crystalline states that have longer lifetimes than ordinary excited states but shorter than the ground state. Using metastable polymorphs can improve properties like solubility and bioavailability. Several techniques to produce metastable polymorphs are described, like seeding, additives, and solvent control. Case studies demonstrate how metastable forms of drugs like famotidine and terazosin hydrochloride were approved generically. Regulatory considerations for showing sameness to the reference listed drug are also covered.

1. Useofmetastablepolymorphtoenhanceoralbioavailability
PRACHI JOSHI
PHARMACEUTICS

2. Introduction
Metastable polymorphs
Preparation of metastable
polymorphs
Effect of metastable
polymorphs
Case studies
Regulatory consideration
Conclusion
contents

3. INTRODUCTION
• A polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two
different arrangements of the molecules of that compound in the solid state.
• Two polymorphs will be different in crystal structure but identical in the liquid and vapor states.
• Polymorphism is the ability of any element or compound to crystallize as more than one distinct crystal
species (e.g., carbon as cubic diamond or hexagonal graphite)
• Different polymorphs of a given compound are different in structure and properties.
• Solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor
pressure, etc., all vary with the polymorphic form.
Haleblian J et. al. Journal of Pharmaceutical Sciences. 1969;58(8):911-29.

4. • Kuhnert-Brandstatter et al., using thermomicroscopic methods have reported on the
polymorphism of steroids, barbiturates and antihistamines
• Mesley et al., using IR spectroscopy, have described the polymorphism of steroids,
barbiturates and sulphonamides.
Compounds No. studied % having polymorphs % of unstable samples
Steroids (m.p. less than
210°C)
48 67 17
Sulfonamides 40 40 23
Barbiturates 38 63 11
Polymorphism of drugs.

5. • Thermodynamically stable form does not always behave as desired in terms of chemical stability or
physical properties such as flowability, filterability, mechanical and morphological properties.
• These physical properties can impact on the manufacturability and the ability to deliver a robust
product to the patients.
• In this case a different solid form that is metastable form may offer the opportunity for improved
physical properties.
• The metastable forms also have better solubility which enhance bioavailability.
• Despite of the stability risk some metastable forms show neglectable or slow kinetics of
transformation to the thermodynamically stable form.

6. Metastable polymorph
Metastable state, in physics and chemistry, particular excited state of an atom, nucleus, or other system that has
a longer lifetime than the ordinary excited states and that generally has a shorter lifetime than the lowest, often
stable, energy state, called the ground state.
Roberts KJ, et. al. Engineering Crystallography: From Molecule to Crystal to Functional Form: Springer Netherlands; 2017.
(a) Schematic of
solubility-supersolubility;
(b) Meta stable zone
width is wider and
nuclei size decreases as
the cooling rate increases

7. • The metastable zone width (MSZW) can be defined as the difference between the maximum solution
concentration in the supersaturated state before crystallisation takes place Cmax and the solution
concentration at equilibrium C∗.
∆Cmax = Cmax – C∗
McCrone rule
• Walter McCrone, a spectroscopist from Chicago, said in 1965 that the number of polymorphs a
compound has is proportional to the amount of money and time that has been spent investigating the
molecule. Carbamazepine is a counter example to McCrone’s rule, as only four polymorphs are known,
despite the extraordinary effort that has gone into investigating its properties. Aspirin is also a counter
example: it has just one known polymorph

8. Metasta
ble
Polymor
ph
Additives
External
effects
Supersatura
tion
Solvent
control
High
throughpu
t
crystalliza
tion

9. Seeding
Soluble
additives
Templati
ng
additives

10. seeding
• Seeding a solution with a crystal of the product is a well-established method to induce crystallization.
• Encourage the formation of particular polymorphs, provided that a seed-crystal of the product.
• Useful to know the width of the metastable zone to use seeding technique successfully.
• Carefully monitoring the moment of nucleation whilst a compound dissolves and re-precipitates during the
heating and cooling cycle.
• Seeding is likely to be effective when the solution is within the metastable zone. If seeding is attempted
when the solution is too dilute, then the seed crystal will dissolve and be lost. If the seeding is tried after
the first traces of nucleation from the supersaturated solution, the effect of the seed may be swamped by
other crystals forming in the solution.

11. • According to Ostwald’s rule first nucleation is likely to lead to a metastable polymorph which
forms through a kinetically driven process.
• Common method to obtain seeds of an metastable polymorph is by quench-cooling of the pure
substance in its liquid form.
e.g. A metastable form of paracetamol (Form II) has been reproducibly obtained by quench-
cooling molten paracetamol.
• Also be used to start the crystallization of single enantiomers from racemic mixtures.
e.g. metastable δ-polymorph of a racemic sulfonate were obtained by adding previously formed
single crystals of the δ-polymorph to a supersaturated solution.

12. Soluble additives
• Tailor-made additives to obtain a
particular crystal form or to inhibit the
growth of an unwanted form.
• Interfere with the nucleation or growth
rates of a particular form.
• Additive has to inhibit, at least, the
fastest growing face of the crystals of
the unwanted polymorph without
affecting the fastest growing faces of
the crystal of the desired polymorphic
form.

13. • Molecular modelling has been useful for designing the right additive.
• Davey et al. selectively inhibited the stable β-polymorph of ʟ-glutamic acid and, hence, favoured
the α-form. This work was based on a molecular mechanics conformation analysis of ʟ-glutamic
acid and of possible additives.
• Reaction by products or impurities present in the system may also have an effect on polymorph
control.
e.g. the metastable form of sulphathiazole is stabilized by the presence of 1 mol% of
ethamidosulphathiazole, a hydrolysis sulphathiazole by product.

14. Targeted
solvents
Supercriti
cal fluids
Mechanic
al
grinding
Solvent
control

15. Targetedsolvents
• Use of solvents or solvent mixtures to promote or inhibit certain crystal motifs.
• Kitamura et al. have studied the effect of solvent in the polymorphic crystallization of BPT
propyl ester . When acetonitrile was used as the solvent, the more stable polymorph was
obtained whereas the metastable form appeared when ethanol and cyclohexane were used.
• Trifkovic et al. showed the crystallization of ranitidine HCl using a non-polar solvent which
leads to strong hydrogen bonding interactions forming a polymorph containing the enamine
tautomer (Form I). When a more polar solvent, such as water or methanol, was used, the
ranitidine–ranitidine hydrogen- bonding interactions were disrupted and the nitronic acid
tautomer (Form II) was obtained.
Kitamura M et. al. Industrial & Engineering Chemistry Research. 2012;51(39):12814-20.
Trifkovic M et.al.. Organic Process Research & Development. 2007;11(1):138-43.

16. Supercritical fluids
• Morphology of solid dosage forms is very important to the pharmaceutical industry.
• Uniform size distribution and sphericity of the powder improve the flow properties and the ease of
making tablets.
• Micronisation reduces the particle size to a few micrometers or even to the nanometer range
increases the surface area and drug dissolution rate, thus increasing its bioavailability.
• Electrostatic charges lead to aggregation and agglomeration which further decreases the drug
performance.
• To avoid these problems and obtain particles with useful characteristics supercritical fluids
technology is used.

17. Supercritical fluid
Rapid expansion of
a supercritical
solution
Supercritical
antisolvent
solution
• Single-step process that is carried out at mild temperatures, and is a green technology because the fluid can
be recovered and recycled.
• By controlling temperature, pressure, flow rate and solvent, different polymorphs can be generated.
Slow expansion of
supercritical solution
Solution enhanced
dispersion by supercritical
solution

18. Crystalliza
tion using
microporo
us
membran
es
pH control
supersaturation

19. Crystallization using microporous membranes
• Paracetamol are known: monoclinic form I is the thermodynamically stable modification at room temperature;
form II (orthorhombic) is metastable at ambient conditions; form III is very unstable.
Di Profio G et. al. Chemistry of Materials. 2007;19(10):2386-8.
pH control
• Polymorph creation controls the level of supersaturation by altering the pH of the solution.
• Method explores the metastable zone, starting from the kinetically driven highest-energy polymorph which
precipitates at high supersaturation, to more stable forms which precipitate at lower supersaturation.
• Metastable polymorphs can be obtained by cycling the system between supersaturation and subsaturation by
pH variation.
• Metastable form is not stable enough to isolate, but from time to time it is stable enough to characterize.

20. Sonocrystalliz
ation
Non –
photochemical
laser induced
nucleation
External effects

21. • Sonication significantly reduces the induction time for nucleation of PABA crystallized in aqueous
solutions.
• Below the transition temperature at 25 °C, the crystallization of the β-polymorph becomes faster
when ultrasound is applied. The induction time decreases with increasing sonication intensity.
• By application of ultrasound, the β-polymorph can also be crystallized above the transition
temperature, as long as the supersaturation is not too high.
Sonocrystallization
Gracin S et. al. Crystal Growth & Design. 2005;5(5):1787-94.

22. High-throughput crystallization
• Pharmaceutical industry needs to test thousands of samples a day using different combinations of temperature,
rate of cooling and heating, concentration, additives, rate of mixing, concentration of excipients and solvents.
• This must all be done in the shortest time possible, and using the smallest amount of compound possible.
• Morissette et al. performed more than two thousand experiments trying to find all polymorphs of the HIV
protease inhibitor ritonavir using only 2 g of the API.
• Characterizing solvents by their physical properties, including Hilderbrand and Hansen solubility parameters, log P,
hydrophile–lipophile balance, boiling point and melting point, and building a 24 solvent library.
• Generated 51 crystalline samples with a hit rate of 2.5%. From these, five different crystalline forms were
identified, including two known polymorphs and three unknown forms.

23. Chemical
stability
Tableting
behaviou
r of
powder
Genericall
y
equivalen
t dosage
form
Effect of metastable
form

24. chemical stability
• While working with aqueous suspensions of experimental corticosteroid some batches of the compound
developed chemical instability.
• X-ray diffraction of starting raw material shows the presence of two different polymorphs.
• Found that one of these polymorphs was light-sensitive.
• Assayed lower than the other batches.
• Slightly different light absorption patterns and one absorb a frequency that causes photochemical
decomposition.
• The patterns would differ slightly and one must absorb a frequency that causes a photochemical
decomposition.

25. Generically equivalent dosage form
• Physiochemical factors influencing the absorption of the anhydrous and trihydrate forms of
ampicillin.
• Aqueous solubility of the anhydrous form was 20% higher than the trihydrate at 37° (10 and 8
mg./ml., respectively).
• In the in vitro experiments the T50 7.5 and 45 min
Haleblian J et. al. Journal of Pharmaceutical Sciences. 1969;58(8):911-29.

26. • Polymorphic forms in the context of guidance (FDA) refer to crystalline and amorphous forms as well as
solvate and hydrate forms, which are described as:
Crystalline forms have different arrangements and/or conformations of the molecules in the crystal lattice.
Amorphous forms consist of disordered arrangements of molecules that do not possess a distinguishable
crystal lattice.
Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If
the incorporated solvent is water, the solvate is commonly known as a hydrate.
• The drug substance in a generic drug product is considered to be the same as the drug substance in the
RLD if it meets the same standards for identity.
Regulatory consideration (concept of sameness)

27. • ANDA must contain information (i.e. chemical name, empirical formula, molecular structure, description) to
show that the active ingredient in the generic drug product is the "same as" that of the RLD.
• Drug product exhibits sufficient stability and is bioequivalent to the RLD
• Drug substance in the generic drug product need not have the same polymorphic form as the drug
substance in the RLD
• FDA has approved a number of ANDAs in which the drug substance in the generic drug product had a
different polymorphic form from the drug substance in the respective RLD (e.g., warfarin sodium,
famotidine, and ranitidine).
• FDA has approved some ANDAs in which the drug substance in the generic drug product differed in solvate
or hydrate forms from the drug substance in the corresponding RLD (e.g., terazosin hydrochloride,
ampicillin, and cefadroxil).

28. Name
Brand
Name
&
Inventor
Dosag
e
form
No. of
polymorphs
Commercial Form
Stabilization of
metastable form
Famotidine
PEPCID;
Valeant
Tablet 3 Form B (Innovator & Generics)
None
High Kinetic stability
Torsemide
DEMADEX;
Meda
Pharma
Tablet 2
Form I (Stable, Innovator)
Form II (Metastable, Generics)
None
Metastable form is
kinetically stable
Barbital
VENORAL;
Bayar
-- 6
Form III
(High kinetic stability)
---
Ranitidine
HCl
ZANTAC;
GSK
Tablet 2
Form II (Stable, Innovator);
Form I (Metastable, Generics)
None
Terazosin
HCl
HYTRIN;
Abbot
Capsule 5
Dihydrate (Stable- Innovator);
anhydrous -I, II, III (Metastable,
Generics)
Moisture control while
mfg & Processing
Carbamazepi
ne
TEGRETOL;
Novartis
Tablet
5
(4 anhydous
forms & a
Dihydrates)
Dihydrate (Stable, Innovator)
β or Form III
(Metastable, Generics)
Packaging Approach
Marketed formulation: metastable polymorph

29. conclusion
• The possibility of detecting drug polymorphism can be viewed in two opposite ways:
o as a risk of clinical failure when an undesired solid state conversion occurs
o as an advantage when more soluble polymorphs may be selected to overcome bioavailability problems
• Thus, the pharmaceutical industry must carefully evaluate the presence of the phenomenon of the
polymorphism for every drugs under development.
• Whenever possible, metastable forms having high solubility that can survive for years without changing to the
stable form are selected for formulation.
• This means that, forms that have considerable activation barrier in moving from metastable state to stable
state would be selected.