INTRODUCTION:

Many a times an API cannot be formulated in its pure form due to various issues of instability. Thus they are converted to solid forms such as polymorphs, salts, solvates, hydrates, amorphous, and co-crystals. Each of them imparts a different physiochemical property and affects other performance. Now a day there is most challanging situation is to enhance solubility of certain drugs. Common problems that challenge the successful drug delivery and manufacture include deficiencies in their properties, such as solubility, stability, bioavailability, organoleptic properties and mechanical properties. It’s easy to solve solubility problem of amorphous form, But difficult for crystalline drug. This review presents the improvement in dissolution profile of drug, bioavailability and solubility by co crystallization technique. Co-crystals basically consists of two components that are the API and the former. Now, the former can be any other excipient or API which when given in combination reduces the dose and also the side effects. Co crystallization is an effective crystal engineering approach various properties of the drug as well as modifying crystal structure. A more refined definition of a co-crystal can be “multicomponent crystal that is formed between two compounds that are solids under ambient conditions, where at least one component is an acceptable molecule or ion”. Some drugs marketed in the form of racemic co crystals include: atenolol, atropine, certirazine, disopyramide, fluoxetine, ketoprofen, loratadine, modafinil, omeprazole, warfare and zopiclone. Pharmaceutical co-crystals are non-ionic supramolecular complexes and can be used to address physical property issues such as solubility, stability and bioavailability in pharmaceutical development without changing the chemical composition of the API. This complex can be formed by several types of interaction, including pi-stacking, hydrogen bonding, and van der Waals forces. For nonionizable compounds co-crystals enhance pharmaceutical properties by modification of chemical stability, mechanical behaviour, moisture uptake, solubility, dissolution rate and bioavailability^{.[1, 2]}.

1. Co-Crystals:

Co-crystals incorporate pharmaceutically acceptable guest molecules into a crystal lattice along with the API. Co-crystals have regained attention as attractive alternate solid forms for drug development (Figure 1). Physiochemical properties of pharmaceuticals can be improved by obtaining co-crystals using co-crystallization ^[3-5].

Co-crystallization is a result of competing molecular associations between similar molecules, or homomers, and different molecules or heteromers. Hydrogen bonds are the basis of molecular recognition phenomena in pharmaceutical systems and are responsible for the generation of families of molecular networks with the same molecular components (single component crystals and their polymorphs) or with different molecular components (multiple component crystals or co-crystals) in the crystalline state^[6].

Figure 1. API solid form classification based on structure and composition

2. Pharmaceutical Co-Crystals:

The physical and chemical property improvements through pharmaceutical co-crystals draw closer the fields of crystal engineering and pharmaceutical sciences. A pharmaceutical co-crystal is a single crystalline solid that incorporates two neutral molecules, one being an API and the other a co-crystal former. Co-crystal former may be an excipient or another drug. Pharmaceutical co-crystal technology is used to identify and develop new proprietary forms of widely prescribed drugs and offer a chance to increase the number of forms of an API. Scientists showed that modifying the physical properties of a pharmaceutical compound through pharmaceutical co-crystal formation improved the performance of a drug known to have poor solubility. Pharmaceutical co-crystallization is a reliable method to modify physical and technical properties of drugs such as solubility, dissolution rate, stability hygroscopisity, and compressibility without alternating their pharmacological behavior^[7,8].

3. Screening Of Co-Crystals:

Co-crystals can be prepared from two molecules of any shape or size having complementary hydrogen bond functionalities. The ability of an API to form a co-crystal is dependent on a range of variables, including the types of co-former, the API co-former ratio, the solvents, the temperature, the pressure, the crystallization technique, etc. Experimental screening for co-crystal formers is not trivial. Synthesis/processing of co-crystals can be accomplished via a number of methods, including slow solvent evaporation crystallization from solution, solvent-reduced (e.g. slurrying, solvent-drop grinding) and solvent-free [e.g. grinding, melt [(hot stage microscopy)], high throughput crystallization and co-sublimation techniques^[9,10,11].

4. Mechanism for Co-Crystal Synthesis:

Amorphous phases generated by pharmaceutical processes lead to co-crystal formation during cogrinding and storage.The mechanisms underlying moisture uptake generated co-crystals of carbamazepine-nicotinamide, carbamazepine-saccharin, and caffeine or theophylline with dicarboxylic acid ligands (oxalic acid, maleic acid, glutaric acid, and malonic acid) when solid mixtures with co-crystal reactants were exposed to deliquescent conditions involve (i) moisture uptake, (ii) co-crystal aqueous solubility, (iii) solubility and dissolution of co-crystal reactants, and (iv) transition concentration. For carbamazepine: nicotinamide co-crystal synthesis, nucleation and growth of co-crystals were directed by the effect of the co-crystal components on reducing the solubility of the molecular complex to be crystallized^[12,13,14].

5. Characterization of Co-Crystals:

Characterization of co-crystals involves both structure (infrared spectroscopy, single crystal x-ray crystallography and powder x-ray diffraction) and physical properties (e.g. melting point apparatus, differential scanning calorimetry, thermogravimetric analysis). The analytical potential of Near Infrared spectroscopy for co-crystal screening using Raman spectroscopy as a comparative method has been reported^[15].

6. Polymorphism of Co-Crystals:

Polymorphism in multi-component crystals is gaining interest in the recent times in the context of pharmaceutical co-crystals. Polymorphs have different stabilities and may spontaneously convert from a metastable form (unstable form) to the stable form at a particular temperature. In addition, they exhibit different melting points and solubilities which affect the dissolution rate of drug and thereby, its bioavailability in the body. Co-crystal polymorphs suggest additional options to modify properties, increase patent protection, and improve marketed formulations. Co-crystals of 4-hydroxybenzoic acid and 2,3,5,6-tetramethyl-pyrazine (2 :1) exhibited the first supramolecular synthon polymorphism in a co-crystal; metastable anti-hierarchic polymorph I was converted to stable hierarchic form II ^[16]

ACKNOWLEDGEMENT:

I simply humble for words to express my heavy debt of gratitude towards my respected guide Assitant Prof. Mrs. B.U. Jain. Appasaheb Birnale College of Pharmacy Sangli, who were gracious enough for sparing time out of her busy schedule to go through project and appreciate it. I also thank our Principal Dr. S.A. Tamboli and Vice -Principal Dr. R. R. Shah, for their kind co-operation in my project work.

I express my gratitude to my colleagues who by their encouragement and advice helped me to present this project. My sincere thanks to all teaching and non-teaching staff who took all efforts in providing me desired necessities for preparation of this project.

There are times in this project when clock beats time and we run out of energy and we want to finish for once forever. Last but not the least our parents made us endures such times with their wishes.

RESULT AND CONCLUSION:

Pharmaceutical co-crystals represent a advantageous class of crystal form in the context of pharmaceuticals. Co-crystals of drugs and drug candidates represent a new type of material for pharmaceutical development. Co-crystals are relatively new to pharmaceutical industry and pharmaceutical co-crystals have given a new direction to deal with problems of poorly soluble drugs. Co-crystals have the potential to be much more useful in pharmaceutical products than solvates or hydrates. The relevance of co-crystals in API formulation includes the ability to fine-tune physical properties, characterization of API, identify and develop new, proprietary forms of prescribed drugs and the opportunity to generate intellectual property. Further research is desirable in order to scale up co-crystal systems and implement manufacturing of final dosage forms on commercial scale. Screening for solid forms is important to guarantee that the optimum form is carried forward in development and to minimize the likelihood of unexpected form conversion. Co-crystals – High Throughput gives vital information on relationship between formation and chemical structure of the API and co-former. Screening of API’s with library of co-crystal formers requires further investigations to include all possible coformers. Studies regarding polymorphism of co-crystals should be strengthened in order to accelerate the development of new pharmaceuticals. Additional developments in screening methodology will further elevate the profile of co-crystals on the pharmaceutical and intellectual property landscapes.

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Received on 01.03.2019 Modified on 19.03.2019

Res. J. Pharma. Dosage Forms and Tech.2019; 11(2):143-146.

DOI: 10.5958/0975-4377.2019.00024.7