A Review of Pharmaceutical

Nano-Cocrystal

Khan Mohammed Anas*,Rehan Deshmukh, Khan Ramiz.V, Mohammad Tauheed

1. JIIU’s Ali Allana College of Pharmacy Akkalkuwa, Dist-Nandurbar -425415, Maharashtra, India

*Correspondence: khanmohammedanas9@gmail.com; Tel.: (+918898761187)

INTRODUCTION

Pharmaceutical companies are constantly working to develop an appropriate dosage form, which is primarily in the solid state. Nevertheless, certain dose forms lack certain physical, chemical, dissolving, and solubility properties. It is a known fact that about 40% of marketed drugs have solubility issues⁽¹⁾. Cocrystals are composed of a variety of molecular interactions, including van der Waals forces, p-p stacking, ionic bonds, and hydrogen bonds. Cocrystals have been shown to be thermodynamically more stable than pristine compound crystals⁽²⁾.Novel medications with good solubility, dissolving rate, mechanical characteristics, hygroscopicity, optimal physical stability, and chemical stability are being developed by numerous pharmaceutical companies and scientists⁽³⁾.

Ø  Crystals :-

A solid whose elements are arranged in a highly ordered microscopic structure to form a crystal lattice that extends in all directions is said to be crystallized.

Ø  Co_crystals :-

Cocrystals are crystalline single phase solids madeup of two or more molecules in a stoichometric ratio that are neither solvents nor simple salts, according to the ideal definition.

Ø  Nano cocrystals :-

Nano cocrystal formulation, which combines the advantage of crystal and cocrystal technologies, have been suggested as a potential strategy to improve oral bioavalablity and dissolving rate.^(1,4)

The biopharmaceutics classification system (BCS) is used to classify active pharmaceutical ingredients (APIs), and intestinal permeability and solubility are identified as key factors influencing the rate and degree of oral bioavailability. In BCS class ii⁽²⁾, the majority of new APIS are categorized as weakly soluble. While formulation techniques for iib pharmaceuticals need to be more soluble, for instance by forming complexes, polymorphs, amorphous forms, and co-crystals, iia drugs are mostly focused on increasing dissolving rates by reducing particle size⁽⁵⁾. Pure drug particles and stabilizers at the nanoscale make up nanosuspensions, also known as nanocrystals. Wet bead milling is a widely used method for preparing nanocrystals. Pure drug particles and stabilizers at the nanoscale make up nanosuspensions, also known as nanocrystals. Wet bead milling is a widely used method for preparing nanocrystals. Nanomedicine is one of the most well-known fields to which nanotechnology has been used, and it has consistently drawn funding and investment. More than 25 nanocrystal medications, primarily organic ones, including ambisome, megace es, visudyne, neulasta, and feridex iv, are currently authorized for use in humans. Generally speaking, nanocrystals will prevent a medicine from breaking down, alter its pharmacokinetic characteristics, or enhance its intracellular distribution and penetration⁽⁶⁾. Various nanosystems have been authorized to improve the solubility of weakly watersoluble medications, more precisely target the pharmaceuticals to the intended site of action, regulate their release, and facilitate better transport across biological barriers. In the EU market, liposomes, nanoemulsions, polymeric therapies, polymeric NPs, nanocomplexes, and nanocrystals are among the nanosystems designed for parenteral or oral drug delivery⁽⁷⁾.

METHOD OF PREPARATION OF NANO COCRYSTAL

Pharmaceutical nano-cocrystals are often prepared using bottom-up and top-down synthesis methods. The two most popular top-down techniques are high pressure homogenization and ball milling, which creates nanoparticles by applying shear pressures⁽¹⁾. One bottom-up method involving nucleation and crystal formation processes is precipitation⁽⁸⁾.

1.TOP DOWN TECHNIQUE:

1.1 High Pressure Homogenization Technique:

High-Pressure Homogenization is another technology that has been applied to reduce the particle size of poorly water-soluble drug molecules⁽¹⁾. It may be used to create pharmaceutical nanocrystals that will enhance drug bioavailability and speed up dissolution.^(3,9).Three fundamental procedures can be distinguished in high-pressure homogenization based on the homogenization apparatus and parameters: (i) Using the jet stream principle, microfluidizer technology (idd-p™ technology); (ii) piston-gap homogenization in water (dissocubes® technology); or (iii) in water mixtures with water-miscible liquids (nanopure® technology).Using a jet stream homogenizer, the Canadian business RTP created the microfluidizer technology, also known as insoluble drug delivery-particles (idd-p™) technology⁽⁷⁾.The HPH method is currently too young for widespread use, despite its ability to successfully create nanosized crystals. The primary drawbacks of HPH are its homogeneous nanoparticle size, high energy consumption, and time commitment⁽¹⁰⁾.

Figure 1. Schematic Representation Of High Pressure Homogenizer⁽⁴⁾.

Ø  According to a study published in the journal of MDPI, this technique is also utilized to create 4-aminosalicylic acid–sulfamethazine nanococrystals⁽¹¹⁾.

Ø  The study, published in the ASIAN journal of pharmaceutical sciences, also uses the high pressure homogenization process to manufacture baicalein nano co-crystals in order to increase the dissolution rate and oral bioavailability of baicalein^(12,13).

1.2 MILLING TECHNIQUE  :-

1.2.1 Solid-State Milling:-

This process produces the majority of the cocrystals. In this procedure, solid cocrystal material is mixed in a stoichiometric ratio using a ball mill and a mortar and pestle. This process takes 30 to 50 minutes. There is no need for a solvent because this is solid state grinding. Because of the decreased fine particle size as a result of this process, the particle's surface area increases⁽¹⁾. It performs exceptionally well in terms of improving selectivity when compared to the dissolution method of creating cocrystals. Furthermore, the process is simple to use and produces cocrystal products quickly⁽³⁾. Although solid-state grinding is an alternate technique that can effectively manufacture nano-cocrystals, it still has certain drawbacks, such as the production and aggregation of particles in the micrometer range⁽¹⁴⁾.

1.2.2 Liquid-Assisted Milling:

As the name suggests, liquid was used in the grinding process to create fine particles^(15,16). This technique involves injecting a tiny amount of solvent during the grinding process to increase the polymorphism of the crystal structure. The solvent's function is to quicken the catalytic process⁽³⁾. Wet media milling can be used since dry milling (such as jet milling) is ineffective at reducing the particle size to the nanoscale range. Wet media milling, sometimes referred to as pearl milling or bead milling, creates an ultrafine particle suspension by dispersing the drug particles in a surfactant/stabilizer solution and subjecting this macrosuspension to milling energy⁽⁷⁾. However, there are drawbacks to liquid-assisted grinding as well, such as low production volume, high energy costs, and subpar product purity results^(17,18).

Ø  Advantages Of Top Down Method:

1.      Simple

2.      Rapid

3.      Avoid organic solvents

4.      High reproducibility

5.      Easy of scale-up

Ø  Disadvantages Of Top Down Method:

1.      Energy-intensive technique.

2.      Potential instability of drugs induced by high shear and temperature.

3.      Product contamination from the grinding media.

2. BOTTOM UP TECHNIQUE:

2.1 Anti Solvent Technique:-

To create nano-sized cocrystals, the anti-solvent precipitation method is an appropriate kind of bottom-up technology⁽¹⁾. When creating nano-cocrystals, the precipitation method is frequently employed, particularly when dealing with a variety of soluble and insoluble component combinations. The successful fabrication of stable nano-cocrystals is a significant problem because of the varying solubilities of cocrystal components in aqueous media⁽¹⁹⁾. In order to achieve stable nano-cocrystals with the required particle size, the anti-solvent system combining stabilizer is chosen and added. The addition of an anti-solvent to the system will increase the likelihood of cocrystal precipitation since cocrystals have differing solubilities in solvent and anti-solvent. The use of this technique in the medical field has been constrained by a lack of systematic research in the selection of anti-solvents. Therefore, the most important step in creating nano-cocrystals is choosing anti-solvents⁽³⁾. The absence of systematic research in the selection of anti-solvents has limited the adoption of this method in the medical field⁽²⁰⁾.One study claims that paclitaxel disulfiram nanococrystals are also made using this technique for effective multidrug resistance and improved apoptosis⁽²¹⁾.

Ø  Advantage Of Bottom Up Technique:

1.      Small particle size

2.      Monodispersed particles

3.      Cost-effective

Ø  Disadvantages Of Bottom Up Technique:

1.      Difficult to scale-up

2.      Time-consuming to find the suitable conditions

3.      Difficult to control the particle growth

4.      Incomplete removal of toxic solvents

According to a research paper published by Heliyon, diclofenac proline nanococrystals are produced using both top-down and bottom-up approaches for development, characterisation, dissolution, and diffusion studies⁽²²⁾.

3.SPRAY DRYING METHOD (SD):

A continuous, cost-effective, and scalable method for creating dry powder is spray drying. created when liquid feed is atomized in an atomizer. Sd has been extensively utilized in the pharmaceutical, cosmetic, and food industries to make as well as pharmaceutical cocrystals. Traditional spray-dryers can't generate
Drug particles under 2 nm in size, yet the B-90 nano spray dryer effectively  creates medication nanoparticles⁽¹⁾. A common method for creating nanocrystals is spray drying. The procedure is using an atomizer to atomize a fluid that contains the medicine in solution into a hot drying gas, usually air⁽⁷⁾.

ü  Another assessment of our work showed that nanosized co-crystals might be produced by applying low-intensity ultrasonic radiation. They demonstrated that sonochemical synthesis can be used to create nano cocrystals and that the sonochemical technique can be applied to general pharmaceutical cocrystals with nanometer-scale dimensions⁽²³⁾.

ü  We have also introduced sonochemistry based on solvent selection and surfactant use to produce pharmaceutical cocrystals of nanometer-scale dimensions in the study of research work on the goal of pharmaceutical nano-cocrystals: sonochemical synthesis by solvent selection and use of a surfactant. The technique takes into account the two constituents of a pharmaceutical cocrystal with a growing number of organic functional groups' intrinsic differences in solubility⁽¹⁵⁾.

ADVANCED CHARACTERIZATION TECHNIQUES:-

1.Thermal Analysis:

 The work titled "Theoretical Foundations of Differential Scalorimeters" states that the DSC has benefits beyond its straight forward operation, speed, and ease of use⁽¹⁾.The qualities of the material as a function of temperature are detected by thermal analysis. As previously mentioned, the most common uses of DSC are in various applications where endothermic and exothermic activities, such as melting point or glass transition temperature, and recrystallization can be identified by monitoring the heat flow. Because it examines both the frequency dependence of thermal events and quasistatic material properties, modulated temperature DSC, or mt-DSC, is more sensitive and has a larger separation capacity with overlapping thermal events. Thermogravimetric analysis, or TGA, is a particularly practical method for determining the precise structure of solvents or hydrates since it measures sample mass while heating⁽¹⁷⁾.  Perkinelmer las gmbh, rodgau, germany) and data were analysed by pyris software (perkinelmer las gmbh, rodgau, germany). 5 ± 1 mg drug powder, physical mixture, macro-co-crystal, nanocrystal and nano-co-crystal freeze dried powder were accurately weighed in 50 μl aluminium pans with pierced lids. The samples were heated at a rate of 10 °C per minute from 20 to 200 °C, and then cooled at a rate of 20 °C per minute to room temperature. A continuously purged dry nitrogen environment (flow rate of 40 ml/min) was used for the test⁽⁵⁾.

2.Molecular Vibration Spectroscopy:

One subfield of molecular spectroscopy, which is further subdivided into raman and infrared (IR) spectroscopy, is molecular vibration spectroscopy. varied crystals have varied bond lengths and angles, as well as different vibration and rotation energies. Thus, various crystals can be distinguished using vibration spectroscopy. . The IR spectrum shows variations in peak form, peak position, peak strength, and band adsorption frequency for different crystals. KBR pellets, the shake-flask method, the film approach, the liquid membrane method, and others are common techniques for preparing IR samples. Currently, the most popular technique for examining medication or food crystals is the kbr pellets approach⁽³⁾.The main benefit of infrared spectroscopy is that it allows us to analyze any sample in any virtual condition. The type of crystal affects the bond length and bond angle, as well as the vibrational and rotational energy. Consequently, vibration spectroscopy can be used to identify different types of crystals⁽¹⁾.

3.Particle Size, Shape and Morphology:

For small particle systems, particle size, size variation, shape, and morphology are crucial indications. As previously mentioned, stability, physicochemical properties such as solubility and dissolution, cell uptake, and ultimate fate in vivo of nanomaterials are all influenced by size, size variation, shape, and morphology. By using a stabilizer layer, drug nanocrystals can be prevented from aggregating. The smaller the particle size, the more likely the particles are to aggregate when considering the impact of particle size and size deviation on stabilization. In a similar vein, particles with a greater size variation and more heterogeneity are also more unstable⁽¹⁷⁾.

ü  A study report that aims to improve the solubility and dissolution rate of poorly soluble pharmaceuticals by combining co-crystal and nanocrystal techniques also uses particle size analysis.⁽⁵⁾

4. Solid-State NMR Spectroscopy:-

Atoms in crystals can have their dynamics, behavior, and chemical environment examined using solid-state NMR spectroscopy. Solid-state NMR spectroscopy is therefore a crucial instrument for analyzing and identifying the crystal formations. The solvates and polymorphs of organic solids were investigated using solid state NMR spectroscopy improved by dynamic nuclear polarization. . The effects of three polymorphs and one hydrated form of the asthma medication theophylline were examined using the NMR technique⁽³⁾.Our research indicates that solid state NMR spectroscopy is an essential method for determining and examining crystal structure.

Formulation Of Nano Co-Crystals And Their Application:-

1.TRICOR:-

Tricor® is recommended for patients with primary hypercholesteremia. It includes the drug fenofibrate and has been sold by Abbott Laboratories in the United States since December 2004. Nanocrystalline particles were produced using Elan's special wet-milling technique, which greatly enhances the drug's solubility properties⁽²⁴⁾.

2. PALIPERIDONE PALMITATE:-

Janssen Pharmaceuticals in Belgium initially offered nano crystals under the trade name invega® sustennatm, which was approved by the FDA in July 2009. This is the first injectable medication for treating schizophrenia that is long-acting and administered once a month. Compared to oral medication therapy, the monthly injection offers a number of advantages, including lowering the risk of relapse brought on by patients skipping their prescriptions⁽²⁵⁾.

ü  A soluble version of a medicine based on the nano-cocrystal (ncc) anti-solvent precipitation technology is described in a report which we reviewed from the European Journal of Pharmaceutics. When compared to pure car, car nccs showed a solubility increase of almost 2000 times. Experiments using DSC and PXRD demonstrated that formulations containing trehalose produced more crystalline structures, whereas those containing peg produced more amorphous ones⁽²⁶⁾.

ü  The European Journal of Pharmaceutics published another study that predicts the release of itraconazole nanococrystals in dogs and demonstrates twice as fast drug release compared to reference drug release data of the itraconazole formulation⁽²⁷⁾.

APPLICATIONS:-

1.      Large surface area nanococrystals can greatly boost a drug's saturation solubility, which in turn speeds up the pace of dissolution.

2.      This innovative drug delivery method allows for the direct incorporation of poorly soluble drugs into tablets, capsules, or hot-melted solid matrices, improving their oral bioavailability.

3.      No hazardous excipients need to be added when using nanococrystals for intravenous administration. Nanococrystals are therefore seen to be a perfect option for intravenous delivery.

4.      Nano co-crystals that are bioavailable and have good solubility have been employed as chemotherapeutic medicines to treat specific types of cancer.

5.      As a consequence, one of the main uses of nanococrystals is in chemotherapy. In this review article published by the Journal of Advanced Scientific Research, we examined how medications containing nanococrystals with exceptional solubility and bioavailability have been used to treat particular cancers⁽¹⁾.

6.      The MDPI has finished and published a study on antiretroviral drugs such lamivudine and zidovudine with the goal of boosting their bioavailability by employing the wet milling method⁽¹⁸⁾.

Figure 2:- Nano Cocrystals Exert Functions On Targeting Cancer Cells⁽⁴⁾.

ADVANTAGES:-

1.      Increased bioavailability as a result of microcrystals' higher saturation solubility and slower rate of dissolution.

2.      Greater adhesiveness compared to microcrystals, which is essential for enhancing the absorption of poorly soluble drugs.

3.      Because there is less aggregation and ostwald ripening (crystal formation) than in microsuspensions, there is more stability.

4.      Better biological efficacy of drugs in all dose forms and ways of administration ^(1,10).

Evaluation Of Nano-Cocrystals:-

1.Solubility Study:-

Solubility studies (n=3) were carried out for the drug, corresponding physical mixture, Cocrystal and nano-cocrystal in 1 % w/v aqueous solution of sodium lauryl sulphate (SLS) by adding in excess to the 5ml vial.  For 72 hours, these vials were maintained at 37°C and 100 rpm in an orbital shaker. By using a UV spectrophotometer to measure absorbance at 305 nm, the drug's concentration was ascertained. A calibration curve for carbamazepine was linear in the range of 5 to 20 μg/ml(y=0.0314x-0.004; r2 = 0.9996; n=3). Nicotinamide did not interfere with the analysis of carbamazepine at 305 nm (figures2)^(5,9).

2.Dissolution Study:-

USP apparatus ii was used to conduct dissolution investigations (n=3) in official dissolving media containing 1% w/v aqueous solution of SLS at 37°C and 75 RPM⁽²⁸⁾. The 900 ml of dissolving media was supplemented with 100 mg of carbamazepine, cocrystal, nano-cocrystal, and physical combination. At a specified period, five milliliters of each sample were taken out and replaced with an equal amount of fresh media that had been warmed to 37°C. After passing through a 0.22 μ filter, the samples were examined for carbamazepine at 305 nm using a UV spectrophotometer. Drug release at 15 minutes (q15), dissolution efficiency (de15) at 15 minutes, and similarity factor (f2) for drug, cocrystal, and nano-cocrystal were all determined using Ddsolver software^(29,30).

CONCLUSION

This study showed that the pharmaceutical sector may find a new and promising way to increase the release rate and absorption of poorly soluble drugs using this innovative nano-cocrystal technology. One innovative method for enhancing the solubility, stability, and bioavailability of medications is the use of pharmaceutical nano-cocrystals. Future drug discovery studies will concentrate on pharmaceutical nano-cocrystals. Pharmaceutical nano-cocrystals are currently the subject of relatively few published studies, particularly a dearth of systematic research on their synthesis and characterization.  In addition to discussing the characterisation technologies utilized to do a detailed analysis of the nano-cocrystals, this review provided a thorough introduction to standard nano-cocrystal manufacturing techniques. There are now a number of documented research avenues in the formulation design of Medicinal nano-cocrystals. We are certain that in the future, pharmaceutical nano-cocrystals will gain popularity for a wider commercial market in the pharmaceutical sector.

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