NEW TRENDS IN THE

CO-CRYSTALLIZATION OF

ACTIVE

PHARMACEUTICAL

INGREDIENTS

Mr. SUJIT S. KALE

M. Pharm (Pharmaceutics)

SMBT College of Pharmacy, Dhamangaon

CONTENTS Introduction. Co-crystals. Co-crystals Vs. solvent. Co-crystallization potential. Preparation methods. Characterization of co-crystals. References.

INTRODUCTION The recent advances in this area have

brought the possibility to produce pharmaceutical materials by design.

Co-crystallization of Active Pharmaceutical Ingredient give improved properties such as dissolution rate and stability under high Relative Humidity and at high temperature.

• Out of the 40% or more NCEs being generated, nearly 60% of them are poorly water soluble.

• These poorly water soluble drugs having slow drug absorption leads to inadequate and variable bioavailability and gastrointestinal mucosal toxicity.

• Therefore, enhancing the aqueous solubility of poorly water soluble drugs is a major challenge for the pharmaceutical researchers.

CO-CRYSTALS:• Pharmaceutical co-crystals can be defined as

crystalline materials comprised of an API and stoichiometric amount of a pharmaceutically acceptable co-crystal former., which are solids at room temperature. 

These can be constructed through several types of interaction including hydrogen bonding, pi-stacking, and van der Waals forces.

• The first known co-crystal Quinhydrone, was studied by Friedrich Wöhler in 1844.

Co-crystals can be divided into:

1- Co-crystal anhydrates

2-Co-crystal hydrates (solvates)

3-Anhydrates of co-crystals of salts

4-Hydrates of co-crystals of salts.

ADVANTAGES OF CO-CRYSTAL

•It is a stable crystalline form as compared

to amorphous solid.

•It can enhance the solubility of poorly

water soluble drugs.

•It can also enhance the bioavailability

due to increased solubility.

•Co-crystal formation technique may be

used for purification steps.

TYPE OF SOLID FORM

Formation of a co-crystal solid often offers scope to transform an amorphous or hard-to-crystallise API into a readily handled, stable crystalline

CO-FORMERS-

Co-formers are the most important components

of the co-crystal.

The co-crystal formation is based on the

structure of the co-formers.

The solubility of co-crystal is also depends on

the solubility of the co-formers.

Some examples like ascorbic acid, gallic acid,

nicotinamide, citric acid , aglutamic acid,

histidine, urea, saccharine,

glycine,tyrosine,valine.

METHODS OF CO-CRYSTAL PREPARATION-1-SOLUTION METHODS-

Evaporative co-crystallizationCooling crystallizationReaction crystallization

2-GRINDING METHODNeat/Dry grinding methodLiquid assisted grinding method

3-ANTISOLVENT METHOD4-SLURRY CONVERSION METHOD5-SUPERCRITICAL FLUID TECHNOLOGY

Grinding method

• Slurry Conversion method Solvent

Crystal

Stirring at R.T.

Decantation Drying PXRD

SUPERCRITICAL FLUID TECHNOLOGY

STEPS INVOLVED IN FORMATION OF CO-CRYSTAL

Selection of API

Selection of co-former

Empirical and theoretical guidance

Co-crystal screening

Co-crystal characterization

CO-CRYSTAL VERSUS SOLVATES The main difference between solvates

and co-crystals is the physical state of the isolated pure components:

if one component is a liquid at room temperature, the crystals are designated as solvates;

if both components are solids at room temperature, the crystals are designated as co-crystals.

CHARACTERIZATION OF CO-CRYSTALS

infrared spectroscopy.

single crystal x-ray crystallography and powder x-

ray diffraction .

physical properties- melting point, differential

scanning calorimetry, thermogravimetric analysis).

pH determination.

Percentage yield.

CO-CRYSTALLIZATION POTENTIAL OF SOME ACTIVE MOLECULES:

By the co-crystallization of antifungal drug itraconazole with 1, 4-dicarboxylic acids (succinic acid, L-tartaric acid or L-malic acid) a modification of the dissolution profile is achieved compared to the amorphous form of itraconazole.

Caffein tends to form hydrates at high RH (relative humidity) while its cocrystals with oxalic acid or malonic acid do not have this unwanted property (never form hydrates) (Jones, 2009).

A 1:1 carbamazepine/saccharin cocrystal compared to polymorph III of carbamazepine (Anticonvulsant Tegretol, Novartis) shows no polymorphous behaviour and is not prone to hydration (Morissete et al., 2007).

PREPARATION METHODS OF CO-CRYSTALS

Co-crystallization by slow evaporation

Crystallization in a slurry

Co-crystallization by freeze draying.

Sublimation

Liquid-assisted grinding

MARKETED PREPARATION-

Pharmaceutical co-crystals of carbamazepine

(Tegretol® )

Pharmaceutical co-crystals of fluoxetine hydrochloride

(Prozac® )

Pharmaceutical co-crystals of itraconazole (Sporanox® )

Pharmaceutical co-crystals of sildenafil (Viagra® ) 

Co-crystals of theophylline

Co-crystals of aceclofenac

Co-crystal of 5-nitrouracil

Co-crystals of indomethacin

REFERENCES Veerendra N, Manvi F, Shamrez Ali. M, B.

Nanjwade, Meenaxi M., New Trends in the Co-crystallization of Active Pharmaceutical Ingredients, Journal of Applied Pharmaceutical Science 01 (08); 2011: 01-05

Cooke C.L, Davey R.J. On the solubility of saccharinate salts and co-crystals. Cryst Growth Des 2008; 8: 3483–3485.

Andrew V, Motherwell S, Jones W,

Pharmaceutical crystallization: Engineering a remedy for caffeine hydration, 05(3);2004: 1013-1021