INTRODUCTION:

The most common state of delivering dosage form is solid such as tablets, capsules, etc. Various other states exists which allow to deliver the API faster than the solid state. But this state provides API in the most convenient, compact and stable format to store. Thus an important part of drug development becomes the understanding and controlling of the solid-state chemistry. Many a times an API cannot be formulated in its pure form due to various issue 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 physicochemical property and affects other performance characteristics stability, bioavailability, purification and manufacturability of the drug in their own better way. Taking this into consideration it is critical to understand the relationship between the particular solid form of a compound and its functional properties.

The maximum development and interest area is being diverted to co-crystallization can be achieved only when the physicochemical properties (Hygroscopicity, solubility and compaction behaviour) of the formulation as a whole is improved. 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. Hence even if the API is the same changing the former will also change the pharmaceutical properties (chemical stability, bioavailability, solubility, melting point etc.)

As mentioned earlier co-crystallization is the most dynamically developing group of solid pharmaceutical substances, it is a very vast area. Hence, they can be divided into: co-crystal anhydrates, co-crystal hydrates (solvates), anhydrates of co crystals of salt and hydrates (solvates) of co-crystals of salts. The according to BCS classification the API belonging to class II and IV have always posed a challenged in case of enhancing the solubility. Hence, one such option is crystallization. Thus the knowledge of crystal engineering along with the molecular properties of API can pose a great option. Co-crystals consists of two or more molecules with a hydrogen bonding. The most appropriate co-crystals can be selected using various Analytical techniques and rational physicochemical studies that include investigations of solubility and stability.

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 a acceptable ion or molecule’’.

Some examples of drugs marketed in the form of racemic cocrystals include: atenolol, atropine, certirazine, disopyramide, fluoxetine, ketoprofen, loratadine, modafinil, omeprazole, warfarin and zopiclone.

Co-crystals differ from salts in such way as; in salts a proton is transferred from the acidic to the basic functionality of the crystallization partner, as the pKa difference between the partners is sufficiently large. In co-crystals, no such transfer takes place. The relationships between various solid forms are shown in (Fig1).

THEORY:

A solid can exist in two forms i.e. crystalline or amorphous. In crystalline form a solid can exist as polymorph, hydrate, solvate, or co-crystal. Mostly we prefer to deliver crystalline forms of active compounds mainly due to the inherent stability of crystalline materials and the impact of crystallization processes on purification and isolation of chemical substances[4]. Pharmaceutical co-crystal is a multiple component crystal in which at least one component is molecular and a solid at room temperature (the co-crystal former), and forms a supramolecular synthon with a molecule or ionic API[5]. A brief summary of the state of the art of pharmaceutical co-crystals is shown in (Fig. 2)[6]

The difference between a co-crystal and a crystalline salt lies merely in the transfer of a proton. Proton transfer from one component to another in a crystal is dependent on the environment. For this reason, co crystals and crystalline salt may be thought of as two ends of a proton transfer spectrum, where the salt has completed the proton transfer at one end and an absence of proton transfer exists for co crystals at the other end.[7]

Co-crystal versus solvates:

The only difference between solvates and co crystals is the physical state of the components. If one of the components is liquid and the other is solid then it is termed as solvates but on the other hand if both exists in solid form then they are termed as co crystals.

Co-crystal versus salt formation:

Salt and co crystal is somewhat confusing. While understanding the difference between a salt and a co crystal. It is very important that pre-formulation activities and chemical/pharmaceutical development aspects should be considered. The important distinguishing points between Salt formations are acid–base reaction between the drug substance and a acidic or basic substance. The advantage of Co crystals that it is an alternative to salts when these do not have ionisable sites in the drug substances (API).

Co-crystallization against Ionization[8]:

There are many other techniques except co- crystallization which may enhance the solubility. One such technique is formation of salts or crystalline ionic complexes but this form posses several inherent drawbacks. The most important requirement for salt formation is the existence of an ionic center of an API of interest. Hence in case of APIs which are non-ionisable these are incapable of salt formation and provide great risk in terms of pharmaceutical profiles.

Different techniques of co-crystallization:

Different techniques are used for the preparation of co crystals they are as follows:

1. Solvent evaporation technique

2. Solid state grinding or mechanical milling technique

3. Solvent reduced technique

a. Slurrying technique

b. Solvent drop technology

4. Hot melt extrusion

5. Ultrasound assisted solution co crystallization.

1. Solvent evaporation technique:

Solvent evaporation is the most conventional method in case of crystallization. In this technique the material is mixed with the common solvent and evaporated completely. In evaporation stage the solution of molecules are expected to undergo various hydrogen bonding reactions. But in case of co-crystallization which consists of API and conformers solubility of both in the selected solvent plays a great role. If the solubility of the two is not similar, then the one with low solubility than the other will precipitate out. This does not mean that solubility alone is the criteria for success. Considering the polymorphism of the compound of interest is also very necessary. If the polymorphism existed then changes are that the compound after co-crystallization may convert into a form which can bridge with the co-former. But the main point to be considered is the ability of the molecule to participate in the intermolecular interaction to form a co-crystal. The intrinsic dissolution rate was increased of Fluoxetine hydrochloride by using multiple conformers like succinic acid, fumaric acid and benzoic acid. Norfloxacin co crystals were synthesized with Isonicotinamide, Malonic acid and maleic acid as conformer. The major disadvantage of this method is that it requires large amount of solvent.

2. Solid state grinding or mechanical milling technique:

Solid state grinding is a technique in which mixing, pressing and crushing materials manually with a mortar and pestle or mechanically in a ball mill. This technique is also called as mechanical milling or neat grinding technique[9]. For example:- Piroxicam co crystals were prepared with help of a 20 carboxylic acid. In this equimolar ratios are taken and physical mixtures were prepared by using mixer mill. Three cycles of 3-5 min. was performed and

determined by Raman spectra[10].

3. Solvent reduced technique:

a. Slurrying technique:

Slurry crystallization is simple process which includes the addition of crystallization solvent in the API along with its acceptable former. The selection of this process is mainly depends upon the physical stability of the crystallization solution to co crystals and its solid former. While preparation of co crystals for Trimethoprim and sulfamethoxazole through slurry technique simple distilled water is used as solvent. Cocrystals designed with 4, 4-Dipyridil of aspirin as a coformer by using slurry crystallization method. However the yield obtained was not sufficient as compared with solvent drop grinding method. The major disadvantage of this method is that it requires large amount of solvent.

b. Solvent drop technology:

Modification of solid grinding technique is this technique where two materials can be grinded by adding a minor quantity of solvent. The criteria of this technique being the solvent added is in very minute quantity which when added acts as a catalyst but does not form a part of the end product. The usefulness of solvent-drop grinding was first demonstrated in the context of co-crystallization rate enhancement in a system involving several co crystals of nitrogenous bases with a cyclohexane tricarboxylic acid derivative, all of which were initially prepared by solution growth. It was found that some co crystals could be readily prepared by solid-state grinding, whereas others exhibited only minor co crystal content after grinding together starting materials for a significant time. For those that did not proceed to completion upon solid-state grinding, it was found that solvent-drop grinding could be used to prepare an essentially phase-pure co crystal material after significantly reduced periods of time.

4. Hot melt extrusion[11]:

Extrusion is useful method for synthesis of co crystals, it involves highly efficient mixing and improved surface contacts, Co crystals are prepared without use of solvent. The selection of this method primarily depends on thermodynamic stability of compound. This method was studied with the use of four models for co crystal formation. Solvent drop extrusion technique used to optimize and make the process more flexible. Solvent drop extrusion technique gives an advantage to carry out process at lower temperature. Hot melt extrusion method was used in synthesis of Carbamazepine- nicotinamide co crystals with polymer as former. Continuous co-crystallization, API and coformer poured in the twin extruder. As a result of continuous addition of mixture the barrel temperature also increases.

5. Sonocrystallization Method[12]:

The development of sonochemical method for preparation of organic co crystals of very finite size has been done. This method was primarily developed for preparation of nanocrystals. Caffeine-maleic acid co crystal preparation commenced with use of ultrasound method. The comparative study of method of preparation of caffeine and theophylline as API and L-tartaric acid as coformer by Solvent drop grinding method and sonochemical method has been commenced. The results of methods were consistent hence Sonocrystallization proves to be a significant approach.

Physicochemical properties:

1. Solubility:

Co crystals of efavirenz were prepared with oxalic acid dihydrate and citric acid monohydrate as coformers using solvent drop grinding method and crystallization by fast evaporation from solvent under a reduced pressure. Equilibrium solubility profile of EFA-OXA and EFA-CITR shows an solubility enhancement of 1.8 and 2.7 folds of efavirenz as compared to commercial sample[13].

2. Bioavailability:

Crystal of API and glutaric acid in a 1:1 molecular ratio was prepared and the single crystal structure is reported. Co crystals shows enhanced aqueous dissolution rate by 18 times as compared to the crystalline form of the drug. Pharmacological studies were carried out on dog. Results confirmed that the co crystal shows increased plasma AUC values by three times at two different dose levels[14].

3. Stability:

Co crystals of an anticonvulsant drug gabapentin with various carboxylic acid conformers were prepared using the reaction crystallization method (RCM). Result shows co crystal of gabapentinare thermodynamically more stable and equal or less soluble than gabapentin hydrate and carboxylic acid coformers in pure water[15].

4. Melting point:

Co crystals of ibuprofen and 4,4-bipyridine was prepared and melting point was determined. The melting points of co crystal were higher than their pure Ibuprofen. This shows improvement in melting point [16] .From this we can resolve problem of hygroscopic drugs.

Characterization of cocrystals:

Various methods used for characterization are as follows:

1. Fourier Transform Infrared (FT-IR) Studies:

2. Crystallographic Method:

3. Thermal analysis:

4. Nuclear magnetic resonance:

5. Scanning electron microscopy:

1. Fourier Transform Infrared (FT-IR) Studies:

In Fourier Transform Infrared (FT-IR) spectrum is taken in range of 400-4000 cm-1. It is a very powerful and useful technique for screening of a co crystal. It is very important tool to determine hydrogen bond formed between acid and base when carboxylic acid is used as a coformer also to determine neutral O-H·N hydrogen bond. The difference between carboxylic acid moiety and carboxylate ion can be determined by IR spectra. The neutral carboxylate ion shows a strong C=O stretching band around 1700cm -1 and a weak C-O stretch near 1200 cm -1. A carboxylate anion (-COO-) shows resonance due to that C-O shows stretch in the fingerprint region around 1000-1400cm -1. In case of neutral O-H···N hydrogen bond shows a two broad stretch around 2450 cm -1 and 1950 cm -1.

2. Crystallographic Method:

Crystallography includes single crystal X-ray diffraction and powder X-ray diffraction. Single X- ray diffraction is used characterize co crystal by measuring distances of hydrogen bond. But to separate a single crystal it is a very hard task in this case a powder diffraction is preferred. X-ray diffraction helps to measure distances between C-O and C=O bond. In carboxylic acid the distance between C=O is nearby 1.2 Å and C-O is nearby 1.3 Å. In case of deprotonation of C-O the resonance which is arising is stabilized by similar distances of bond. By comparing X-ray data of drug, coformer and co crystal we can confirm formation of co crystals[17].

3. Thermal analysis:

Differential Scanning Calorimetry:

Differential Scanning Calorimetry (DSC) is one of the most widely used thermal analytical method of analysis. There are a number of thermal analysis techniques which can be employed including: Differential Scanning Calorimetry (DSC), Differential Thermal Analysis (DTA), Thermo Gravimetric Analysis (TGA), Derivative Thermogravimetry (DTG) and Evolved Gas Detection (EGD). These techniques are based on the principle of measuring the changes in physical properties of a substance as a function of temperature when that substance is subjected to a controlled temperature program. Differential scanning calorimetry is now the most widely used method for the characterization of a solid dispersion. Differential Scanning Calorimetry (DSC) is defined as “A technique in which a difference in the heat flow (power) to the sample (pan) and reference (pan) is monitored against time or temperature while the temperature of the sample, in a specified atmosphere, is programmed”. The plot obtained from the DSC instrument is seen as a differential heating rate versus temperature or time (Joules/second or Calories/second).

4. Nuclear magnetic resonance:

Solid state nuclear magnetic resonance is used to characterize co crystals. In this method chemical environment of nuclei of different polymorphs are studied due to magnetic non- equivalence. The resonance peak is different for different polymorphs having magnetically non- equivalent nuclei[18].

5. Scanning Electron Microscopy:

Scanning electron microscopy is used to characterize surface morphology of the particles. Surface morphology of drug, coformer and co crystal is useful for comparison and to determine change of morphology. The sample is analyzed by mounting sample on double sided adhesive tape that has been previously secured on copper stubs. Voltage of 10kV is used during analysis.

Regulatory classification of pharmaceutical cocrystals:

At present there is no regulatory paradigm exists governing co crystal forms. Co crystals are the intermediate between hydrates (ANDA-eligible) and salts (ANDA-noneligible). Co crystals are classified as per the Agency‘s current regulatory framework as dissociable API—excipient molecular complexes with the neutral guest compound being the excipient. Cocrystals in the brief defined as the molecular association of Active Pharmaceutical ingredient(API) and its excipients occurs within the crystal lattice. In this way, an Active Pharmaceutical ingredient (API) that has been reacted with a co crystallizing excipient to generate an API and its excipients complex. If the approval of new co crystal is via new drug applications (NDAs) and abbreviated new drug applications (ANDAs) will create impact on overall use of co crystal technique by pharmaceutical industry[19].

Pharmaceutical co-crystals as intellectual property:

Compared to other classes of solid forms, co-crystals possessed particular scientific and regulatory advantages, and alongside these advantages were intellectual property issues which give co-crystals with unique opportunities and challenges. Researchers reported the importance regarding patents on Pharmaceutical co-crystals to the pharmaceutical industry. The value of co-crystals to the pharmaceutical industry should become clearer, mainly with respect to several relevant legal and regulatory issues, as products containing co-crystal technology come out from pharmaceutical development pipelines onto the market.

Advantages of co crystal approach:

Co-crystals having several advantages, such as no necessitate to make or break covalent bonds, as compared to amorphous solids it is stable crystalline form, theoretical ability of all types of drug molecules such as weakly ionisable/non-ionisable to form co-crystals, the existence of numerous potential counter-molecules such as food preservatives, pharmaceutical excipients, additives, and other APIs, the only solid form that is designable via crystal engineering patentable expanding Ipportfolios and can be produced using solid-state synthesis green technologies high yield, no solvent or by-products.

Applications of co-crystals:

Compared to other solid-state modification techniques employed by pharmaceutical industry, co-crystal formation appears to be an advantageous alternative for drug discovery (e.g. new molecule synthesis, nutraceutical co-crystals), drug delivery (solubility, bioavailability) and chiral resolution. Experts are of the opinion that pharmaceutical intellectual property landscape may benefit through co-crystallization.

CONCLUSION:

Pharmaceutical cocrystals are a class of solid forms with lot of advantages like fine tune properties of drug. Cocrystal has ability to fine tune Physicochemical and biopharmaceutical properties. Cocrystal due to their large advantages attracted the interest of Pharmaceutical researcher‘s and Pharmaceutical industry. Patentability also has gained lot of interest of Pharmaceutical industry. As concern with the Studies of polymorphism of cocrystals should be strengthen in order to promote the development of new pharmaceuticals. The value of cocrystalsis clear to a Pharmaceutical industry with respect to regulatory aspects, and also capable for developing pipeline onto the market.

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Received on 28.12.2015 Accepted on 28.01.2016

Asian J. Res. Pharm. Sci. 6(1): Jan.-Mar., 2016; Page 51-58

DOI: 10.5958/2231-5659.2016.00008.4

Resent case studies of pharmaceutical co crystals
API	Coformer	Description
Spironolactone (SPI (nonionizable drug)	Saccharin	It is 1:1 co crystal hemihydrates, having improved solubility than SPI form II which is most stable.
Carbamazepine	Saccharin	Solvate formation suppressed by using solvent mixtures, that they reduce the solubility differences between different compounds as compared to pure solvents.
Caffeine	1.Maleic Acid 2.Glutaric Acid	1.Reported 1:1 and 2:1 cocrystals together with a new polymorph of maleic acid and rationalize this behavior through measurement of the binary and ternary phase diagrams. 2.The phase diagram of caffeine-glutaric acid-acetonitrile in the temperature range of 10-35 0 C was charted using ATR-FTIR and has laid the foundation for further co-crystallization process development of the model system.
2-chloro-4- Nitro benzoic acid	Nicotinamide	It is 1:1 cocrystal associated via a carboxylic acid–pyridine hydrogen bond, Thermally more stable than the pure drug.
Sulfamethazine	Theophylline	The sulfamethazine molecules form a dimer through the intermolecular hydrogen bonding (O...H-N), and two intermolecular hydrogen bonds (O...H-N and N... H-N) keep the theophylline attached the dimer.
Acetaminophen	2,4 pyridinedi- Carboxylic Acid	Red colored co crystal discovered by screening using the solution-mediated phase transformation technique.

ABSTRACT: