INTRODUCTION

The development of an acceptable dosage form, which is predominantly in the solid state, is a continuous effort by pharmaceutical companies. [1] Pharmaceutical crystal are materials considered to have crystallized if its constituents are organized in a highly ordered microscopic structure to create an all-pervasive crystal lattice.Pharmaceutical Co-crystal are crystallized single phase solid composed of two or more molecules in a stoichiometric ratio that is neither a solvent nor a gas According to the ideal definition, simple salts. [2]

Pharmaceutical Nano-cocrystal formulations, which combine the advantages of cocrystal and nanocrystal technologies, have been suggested as a potential strategy to improve oral bioavailability and dissolving rate. To our knowledge, however, there have only been a few studies on nano crystals, specifically those involving the nano-cocrystal formulations of itraconazole-adipic acid, indomethacinsaccharin, furosemide-caffeine, and myricetin nicotinamide. Compared to cocrystals, nano-cocrystals can further increase a drug's solubility by having crystals in the nanometer size range. Furthermore, several scientists claimed that nano-drugs are usually disseminated to increase their stability. [3]

The basic components of these pharmaceutical cocrystals are cocrystal former (CCF) and API. Covalent bonds or hydrogen bonds are used to bind these compounds together. The API and the co crystal former are both said to have existed in a solid state by many accounts, but by exception, some accounts include liquid components that are present at ambient temperature. [4]

Cozcrystals, solid molecular-scale combinations of several compounds, are intended to be custom-made materials with more employability than their pristine individual constituents in industries like explosives and medicine. Cocrystals are created in the medical field by crystallizing pharmaceutical active components with carefully selected coformers to provide drugs with improved stability, high solubility, and thus high bioavailability and optimum drug uptake. Scaling up may enhance these properties even more because nanoparticles have a higher surface to volume ratio than their micron-sized cousins. [5]

pure solid substance Drug Nano crystals are composed of nanoparticles wrapped in a stabilizer layer. A stabilizer is rarely required. However, a layer of polymer and surfactant is mostly needed to stabilize nanoparticles against particle aggregation. The stabilizer layer can be made up of just one element, but it's also typical to use a mix of components, like a polymer and a surfactant. The stabilizing layer can be given some functional/linking groups to provide drug nano crystal functionality. Solid micelles are frequently used to describe nano crystals. [6]

APPROACH FOR NANO CRYSTAL

Salt generation, complexation, solubilization, pH control, chemical modification, and liposomal delivery are only a few techniques for improving solubility. The widespread use of these conventional procedures is hindered by certain limitations, such as the limited solubilizing agents' capability, the altered pharmacological efficacy of pharmaceuticals following chemical modification, and the poor physical & chemical stability of liposomes. Furthermore, drugs must possess specific properties including sufficient ionizing ability, solubility in specific organic solvents, and acceptable molecular size or structure. [7]

Investigating fresh approaches to these problems is urgently needed, and nano crystallization for particle size reduction has proven to be a practical technique. Poorly soluble drugs are successfully reduced to micrometer-sized particles using the micronization process, which also improves the surface-to-volume ratio and, ultimately, the rate of bioavailability. However, micronization is less successful in reaching the appropriate bioavailability for highly lipophilic medicines due to air entrapment and low wettability. Thus, the process of "nanonization," or turning micronized particles into nanoparticles, is a useful development. [8,9]

PROPERTIES OF NANO COCRYSTALS

v  Hygroscopicity and hydrate formation

Cocrystals can change the API's hygroscopicity. This was demonstrated by 17 Caffeine cocrystals, a nonstoichiometric crystalline hydrate of caffeine that included about 0.8 moles of water for every mole of caffeine. Anhydrous or crystalline caffeine powder was converted to caffeine hydrate at a high relative humidity (98%). Contrarily, when the relative humidity is low, caffeine hydrate loses its hydration water and transforms into caffeine. During CSD's research, just one caffeine salt form that is suitable for pharmaceutical use was found: a hydrochloride dehydrate. [18]

v  Melting point

The melting points of individual crystals vary from those of cocrystals due to molecular interactions.17 This was shown by the Indomethacin-Saccharin cocrystal. Around 184°C is the melting point of IND-SAC cocrystals. Indomethacin (162°C) and saccharin (225-227°C) also melt within this range. The creation of a new crystalline phase is indicated by the unusual melting point of IND-SAC cocrystals. One endothermic transition in the IND-SAC cocrystals proves the phase's absence of any unbound or absorbed solvent or water as well as its stability up until melting point. [19]

v  Chemical stability

The chemical stability of an API can benefit from cocrystallization.^[17] As demonstrated, solvothermal techniques were used to crystallize carbamazepine cocrystals containing nicotinamide and saccharin CBZ: NCT in (1:1), which had improved chemical stability after photoirradiation and better physical stability after extended exposure to relative humidities of 75% at 22° C.20 When CBZ is cocrystallized with coformers like saccharin (SAC) or nicotinamide (NCT), the molecular connections and packing arrangement of the CBZ molecules are changed. These cocrystals are therefore more resistant to hydration and breakdown. [17]

v  Dissolution rates and solubility

Cocrystals have an impact on the solubility and rate of dissolution of crystalline medicines. As seen in the illustration, fumaric, succinic, and benzoic acids were combined to create cocrystals of the antidepressant Fluoxetine hydrochloride. Powder dissolution tests revealed that the cocrystals dissolved easily in water at 20°C. Cocrystals and crystalline salt dissolving rates were compared using intrinsic dissolution rate studies. In contrast to the Fluoxetine-benzoic acid 1:1 cocrystal, which dissolved at half the rate, the 2:1 Fluoxetine-fumaric acid cocrystal dissolved at the same rate as pure crystalline Fluoxetine hydrochloride. The succinic acid-fluoxetine hydrochloride 2:1 cocrystal dissolved at a rate that was roughly three times faster, while it was unable to measure the rate precisely. As a result, cocrystal synthesis with different ligands allows for customization of medication dissolution rates. [21]

METHODS OF PREPARATION of NANOCOCRYSTAL

We are now in the exploratory stage of developing dependable Nano-co-crystal formulation preparation processes. When preparing pharmaceutical Nano suspensions, such as those that are already on the market, bead milling is the more trustworthy approach when compared to crystallization procedures for creating Nano-co-crystals. Instability during and after preparation can be reduced by using a medium with low solubility for milled compounds and allowing for proper cooling [10]. Nano-cocrystals can be produced by both top-down and bottom-up techniques, such as ball milling and precipitation. [11]

v  Top-down synthesis

Ø  Milling

Solid state grinding

This technique is used to manufacture the majority of cocrystals. In this procedure, solid cocrystal material is mixed in a stoichiometric ratio using a mortar and pestle and a ball mill. This process takes 30 to 50 minutes. Solvent is not required because this is solid state grinding. Due to the reduced fine particle size, this process results in an increase in particle surface area. [12]

Liquid state grinding

The method used liquid for grinding to create fine particles, as the name suggests [13].  This method is a viable choice for the production of cocrystals with a high degree of purity. Polymorphic cocrystals only occasionally form. By adding solvents with different polarity, the crystalline polymorph form can transform into another organic compound. [4]

Ø High Pressure Homogenization

High pressure homogenization (HPH), which is widely employed to manufacture medicinal Nano sized crystals, has the potential to hasten the dissolving procedure and improve drug bioavailability. Using poloxamer 188 as a stabilizer, the HPH approach has been utilized to produce nano-cocrystals of BE (Baicalein) Nano crystals and BE-NCT (Baicalein nicotinamide). [3]

v Bottom up technique

The Anti-solvent Precipitation Method (EMAMI) is a suitable bottom-up methodology kind of method for producing Nano sized cocrystals [4] There hasn't been much systematic research done on choosing anti-solvents, which has limited the application of this strategy in the medical field.

v Precipitation technique

A nanocrystal is a pure solid particle with a mean diameter of one micrometer. In order to precipitate water-insoluble medicine and water-soluble coformer nano-cocrystals, Pradip Thakor set out to develop a procedure. This work made use of the carbamazepine nicotinamide model crystal. [15]

FORMULATION OF NANO COCRYSTALS AND THEIR APPLICATIONS

TRICOR®                       

Tricor® should be taken by patients with primary hypercholesteremia. Abbott Laboratories has been selling it in the USA since December 2004. It contains the API fenofibrate. The production of nanocrystalline particles by Elan's distinctive wet-milling process considerably enhances the properties of the drug's solubility.

Paliperidone palmitate

The long-acting, monthly injectable solution is the first of its kind for the treatment of schizophrenia, and was introduced by Janssen Pharmaceuticals in Belgium under the brand name Invega® SustennaTM. The monthly injection offers several advantages over oral drug therapy, such as preventing the possibility of relapse brought on by patients failing to take their prescription. [16]

CHARACTERIZATION TECHNIQUE FOR THE NANOCOCRYSTAL

Molecular Vibration Spectroscopy

The biggest benefit of IR (Infra-Red) spectroscopy is that it allows us to investigate any sample almost in any state. Depending on the type of crystal, different vibrational and rotational energies, bond lengths, and bond angles exist. As a result, vibration spectroscopy can be used to distinguish between different crystals [4]

Thermal Analysis

Theoretical Fundamentals of Differential Scanning Calorimeters states that the DSC is not only quick and easy to use, but also has other benefits. [15]

Microscopy Technique

The molecular level chemistry of cocrystals is determined using a variety of analytical techniques. We mostly employ either of the two techniques, namely the transmission electron microscopy (TEM) or the atomic force microscope (AFM), for the characterisation of nanococrystals. [17]

Solid state NMR spectroscopy

Solid-state NMR spectroscopy allows the kinetics, behaviors, and chemical surroundings of atoms in crystals to be investigated. In order to investigate and identify crystal structures, the Pinon method relies heavily on solid-state NMR spectroscopy. [18]

Nano co-crystal in chemotherapy

Chemotherapy is an effective way to treat cancer. This medication has a flaw that prevents widespread use: drug resistance. As a remedy to this issue, numerous specific cytotoxic drugs for cancer cells are constantly being created. However, many of them have poor solubility and in vivo bioavailability. Specific tumors have been treated with chemotherapy drugs consisting of Nano crystals that have improved solubility and absorption. Meghna used pressure homogenization techniques, namely the high pressure homogenization technique, to generate Nano suspension PIK75. Results showed that Nano suspension PIK75 has an 11-fold increase in saturation solubility and better plasma stability. [13] The targeting, bioavailability, and drug residence durations at the target site were all improved in nevirapine solutions with nano crystal modifications. [19] Overall, the nano co-crystal represents an improvement over cytotoxic drug-based chemotherapy as a method of treatment. Treatment of neoplasms with nanocrystal and NCC technologies has proved successful [20]

In-vitro release Study

In-vitro drug release tests were carried out using a USP Type II dissolution machine with a 50 rpm rotation speed. The preparation was kept at a temperature of 37 0.20 °C and submerged in 900 ml of phosphate buffer solution in a vessel. 5 ml of the required medium were withheld at certain intervals and replaced with the same amount of dissolving medium in the flask to maintain a constant volume. A UV spectrophotometer was used to evaluate the samples that were withheld. [22]

ADVANTAGES OVER NANO CO-CRYSTALS

Ø  Higher bioavailability as a result of the slower rate of dissolution and higher saturation solubility of microcrystals.

Ø  High adhesiveness in comparison to microcrystals, a crucial factor in improving the absorption of medications that aren't very soluble.

Ø  More stable than microsuspensions due to the absence of aggregation and Ostwald ripening (crystal formation).

Ø  Better biological performance of drugs in all dose formulations and delivery systems. [21]

CONCLUSION

The objective of the review was to investigate how the Nanococrystallization process improved the solubility and dissolution rate of drugs that were not water soluble. A revolutionary strategy has been employed to increase the solubility, stability, and bioavailability of medications: pharmaceutical nano-cocrystals. Evaluations conducted both in vitro and in vivo point to the nano-cocrystals as a cutting-edge method for improving the bioavailability and dissolution rate of poorly soluble natural compounds. This review included both the characterisation techniques that were used to carefully investigate the nano-cocrystals as well as the processes used to produce them. Pharmaceutical nano-cocrystals will be more widely used in the pharmaceutical industry in the future, we are confident.

ACKNOWLEDGEMENT

We are thankful to the Principal and Management of JIIU’s  Ali-Allana College of Pharmacy Akkalkuwa, Dist- Nandurbar  for providing moral support and necessary facilities during completion of this work.

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