Download - Co crystalization
![Page 1: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/1.jpg)
NEW TRENDS IN THE
CO-CRYSTALLIZATION OF
ACTIVE
PHARMACEUTICAL
INGREDIENTS
Mr. SUJIT S. KALE
M. Pharm (Pharmaceutics)
SMBT College of Pharmacy, Dhamangaon
![Page 2: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/2.jpg)
CONTENTS Introduction. Co-crystals. Co-crystals Vs. solvent. Co-crystallization potential. Preparation methods. Characterization of co-crystals. References.
![Page 3: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/3.jpg)
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.
![Page 4: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/4.jpg)
• 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.
![Page 5: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/5.jpg)
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.
![Page 6: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/6.jpg)
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.
![Page 7: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/7.jpg)
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.
![Page 8: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/8.jpg)
TYPE OF SOLID FORM
![Page 9: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/9.jpg)
Formation of a co-crystal solid often offers scope to transform an amorphous or hard-to-crystallise API into a readily handled, stable crystalline
![Page 10: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/10.jpg)
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.
![Page 11: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/11.jpg)
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
![Page 12: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/12.jpg)
Grinding method
• Slurry Conversion method Solvent
Crystal
Stirring at R.T.
Decantation Drying PXRD
![Page 13: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/13.jpg)
SUPERCRITICAL FLUID TECHNOLOGY
![Page 14: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/14.jpg)
STEPS INVOLVED IN FORMATION OF CO-CRYSTAL
Selection of API
Selection of co-former
Empirical and theoretical guidance
Co-crystal screening
Co-crystal characterization
![Page 15: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/15.jpg)
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.
![Page 16: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/16.jpg)
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.
![Page 17: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/17.jpg)
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.
![Page 18: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/18.jpg)
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).
![Page 19: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/19.jpg)
PREPARATION METHODS OF CO-CRYSTALS
Co-crystallization by slow evaporation
Crystallization in a slurry
Co-crystallization by freeze draying.
Sublimation
Liquid-assisted grinding
![Page 20: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/20.jpg)
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
![Page 21: Co crystalization](https://reader033.vdocuments.net/reader033/viewer/2022051322/5463dbccb4af9f583f8b4710/html5/thumbnails/21.jpg)
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