Dissolution Rate Of Cocrystals Research Articles

SOLUBILITY ENHANCEMENT TECHNIQUE FOR BCS CLASS II DRUG - ONDANSETRON HYDROCHLORIDE BY CO-CRYSTALLIZATION METHOD

The present study was aimed to increase solubility of ondansetron hydrochloride by preparing co-crystals by co-crystallization method using various co-formers. Co-crystals of ondansetron HCl were prepared using co-formers such as benzoic acid, aspirin, benzamide, para amino benzoic acid (PABA), urea and citric acid by solvent evaporation method. Co-crystals were characterized by FTIR, DSC, XRD and SEM. The solubility of ondansetron co-crystals was significantly higher than that of pure ondansetron HCI. The dissolution rate of co-crystals reported were in the range of 63-99% compared with pure ondansetron HCl i.e., 38.70% within 30 min. The FTIR indicated a shift in the characteristic peaks of the co-crystals but did not suggest any interaction between the co-former and the drug. DSC data indicated a change in the endotherm, resulting in a new melting point of the co-crystals. The XRD spectra demonstrated the presence of different crystalline phases. Besides, SEM demonstrated the formation of different solid phase in presence of co-formers.

Synthesis, Characterization, and Stability Optimization of Ibuprofen Cocrystals eEploying Various Hydrophilic Polymers.

Cocrystals are an efficient way for the delivery of low soluble drugs but when dissolved they rapidly disproportionate. To formulate the cocrystals in tablets, cocrystals must be stabilized. In this study ibuprofen-nicotinamide (IBU-NIC) cocrystals were synthesized initially by slow solvent evaporation and for bulk production by fast solvent evaporation techniques. The cocrystals were characterized by powder X-ray diffraction (PXRD), Fourier transform infrared spectrophotometer (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and optical microscopy. The ibuprofen cocrystals showed greater solubility compared to the parent drug. Intrinsic dissolution data was utilized for efficacious screening of tablet formulations. Using hydrophilic polymers at a ratio of 6:1 (polymer to IBU-NIC cocrystal ratio), hydroxypropyl methylcellulose (F1), polyvinylpyrrolidone (PVP) K-30 (F2) and PVP K-90 (F3), three tablet formulations were prepared that stabilized cocrystals during dissolution. The drug release profiles after 60 minutes from formulations F1 (92.30), F2 (98.54), F3 (99.88) were all higher compared to the marketed brand BRUFEN® F, (79.61%) in a simulated intestinal media (p<0.001). Significant increase in the dissolution rate of cocrystal was observed with no phase change in all formulations.

Cocrystals of carbamazepine: Structure, mechanical properties, fluorescence properties, solubility, and dissolution rate

Carbamazepine (CBZ) is an anticonvulsant with very low water solubility, presenting as a white crystalline powder with poor mechanical properties and is hard to bend. To enhance CBZ’s physicochemical properties, such as water solubility and mechanical properties, we selected six cocrystal coformers (CCFs): nicotinamide (NIC), benzamide (BZM), salicylic acid (SCA), fumaric acid (FMA), trimesic acid (TMA), and hesperetin (HPE). Six CBZ cocrystals were successfully prepared using the solution method. Fourier transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and single crystal X-ray diffraction (SCXRD) were used to characterize the crystal structures and gain comprehensive insights into the six cocrystals. The mechanical, fluorescence, and solubility properties of the six cocrystals were tested. The results reveal that most of the prepared cocrystals exhibit improved water solubility and mechanical properties when compared to CBZ. Among them, the dissolution rate of cocrystals excluded from CBZ-HPE has increased by an average of 3 or 4 times compared to CBZ, while CBZ-HPE exhibits superior mechanical properties. Moreover, all six cocrystals possess better fluorescence performance than CBZ. We thoroughly evaluated the mechanical properties of the cocrystals through both experimental and theoretical approaches. This work provides a new direction for studying drug cocrystals to improve the physicochemical properties of drugs.

In Vitro-In Vivo Correlation in Cocrystal Dissolution: Consideration of Drug Release Profiles Based on Coformer Dissolution and Absorption Behavior.

This study assessed the in vitro-in vivo correlation in cocrystal dissolution based on the coformer behavior. 4-Aminobenzoic acid (4ABA) was used as a coformer. Cocrystals of poorly water-soluble drugs with 4ABA, ketoconazole cocrystal (KTZ-4ABA), posaconazole cocrystal (PSZ-4ABA), and itraconazole cocrystal (ITZ-4ABA) were used. These three cocrystals generated supersaturated solutions in fasted state simulated intestinal fluid (FaSSIF) in a small-scale, 8 mL dissolution vessel. The time profile of the dissolved amount of 4ABA, an indicator of cocrystal dissolution, was significantly different among the three cocrystals. Under the conditions utilized, half of the KTZ-4ABA cocrystal solid rapidly dissolved within 5 min and the dissolved amount (% of applied amount) of KTZ and 4ABA was the same. Then, even though the residual solid cocrystal gradually dissolved, KTZ precipitated with time. The PSZ-4ABA cocrystal dissolved in a linear fashion with time but the dissolved concentration of PSZ reached a plateau in the supersaturated state and was maintained for at least 2 h. The dissolution rate of ITZ-4ABA was very slow compared to those of the other cocrystals, but a similar tendency was observed between cocrystal dissolution and the dissolved amount of ITZ. The rank order of the cocrystal dissolution rate based on the conformer concentration was KTZ-4ABA > PSZ-4ABA > ITZ-4ABA. Furthermore, cocrystallization of the three drugs with 4ABA significantly enhanced the oral drug absorption in rats. The rank order of the in vivo cocrystal dissolution rate by a deconvolution analysis with the plasma concentration-time profile of 4ABA was KTZ-4ABA > PSZ-4ABA > ITZ-4ABA, which corresponded well with the in vitro dissolution profiles of the cocrystals. These results indicate that analysis of cocrystal dissolution based on the coformer behavior may be useful to evaluate the in vitro and in vivo cocrystal dissolution.

Enhancement of Dissolution Rate and Bioavailability of Nifedipine by Chitosan Based Cocrystallization Technique

The objective of present study was to enhance solubility and dissolution behaviour of nifedipine by using cocrystallization method. A significant increase in solubility and dissolution rate of nifedipine has been demonstrated by solvent change method using chitosan. In this method, chitosan was precipitated on nifedipine crystals using sodium citrate as a salting out agent. An accurately weighed chitosan was dissolved in 1% acetic acid and drug was added in the chitosan solution. This resulting solution was added drop wise into 1% sodium citrate solution with continuous stirring. Sodium citrate precipitate polymer on drug crystals. FTIR, DSC, XRD, SEM, In-vitro dissolution studies, were studied for characterization of prepared cocrystals. Stability studies showed a good stability character of prepared cocrystals. Design Expert® software version 10.0 was used to develop polynomial models which were analysed to delineate the main effects for each CQA (critical quality attributes) through Box-Bhenken design expert. Pharmacokinetic study clearly showed the enhancement of dissolution rate of cocrystals. The above investigation concluded that the significant dose reduction is possible for nifedipine with cocrystal formulation which leads to improve patient compliance.

The role of pH and dose/solubility ratio on cocrystal dissolution, drug supersaturation and precipitation

Cocrystals that are more soluble than the constituent drug, generate supersaturation levels during dissolution and are predisposed to conversion to the less soluble drug. Drug release studies during cocrystal dissolution generally compare several cocrystals and their crystal structures. However, the influence of drug dose and solubility in different dissolution media has been scarcely reported. The present study aims to investigate how drug dose/solubility ratio (Do=Cdose/Sdrug), cocrystal solubility advantage over drug (SA=Scocrystal/Sdrug), and dissolution media affect cocrystal dissolution-drug supersaturation and precipitation (DSP) behavior. SA and Ksp values of 1:1 cocrystals of meloxicam-salicylic acid (MLX-SLC) and meloxicam-maleic acid (MLX-MLE) were determined at cocrystal/drug eutectic points. Results demonstrate that both cocrystals enhance SA by orders of magnitude (20 to 100 times for the SLC and over 300 times for the MLE cocrystal) in the pH range of 1.6 to 6.5. It is shown that during dissolution, cocrystals regulate the interfacial pH (pHint) to 1.6 for MLX-MLE and 4.5 for MLX-SLC, therefore diminishing the cocrystal dissolution rate dependence on bulk pH. Do values ranged from 2 (pH 6.5) to 410 (pH 1.6) and were mostly determined by the drug solubility dependence on pH. Drug release profiles show that maximum supersaturation (σmax=Cmax/Sdrug)and AUC increased with increasing Do as pH decreased. When Do>>SA, the cocrystal solubility is not sufficient to dissolve the dose so that a dissolution-precipitation quasi-equilibrium state is able to sustain supersaturation for the extent of the experiment (24 h). When Do<<SA, cocrystal solubility is more than adequate to dissolve the dose. Low σmax values (1.7 and 1.5) near the value of Do (2.3 and 2.4) were observed, where a large fraction of the cocrystal added is dissolved to reach σmax. Two different cocrystal to drug conversion pathways were observed: (1) surface nucleation of the metastable MLX polymorph IV on the dissolving cocrystal preceeded formation of the stable MLX polymorph I in bulk solution (in all conditions without FeSSIF), and (2) bulk nucleation of the stable MLX polymorph (in FeSSIF). The interplay between cocrystal SA, Do, and drug precipitation pathways provide a framework to interpret and understand the DSP behavior of cocrystals.

Understanding the Effects of a Polymer on the Surface Dissolution of Pharmaceutical Cocrystals Using Combined Experimental and Molecular Dynamics Simulation Approaches.

The molecular interactions between the surfaces of cocrystals [i.e., flufenamic acid and theophylline (FFA-TP), flufenamic acid and nicotinamide (FFA-NIC), and carbamazepine and nicotinamide (CBZ-NIC)] and the polymers [i.e., polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and copolymer of vinylpyrrolidone (60%)/vinyl acetate (40%) (PVP-VA)] were investigated through combined experimental and molecular dynamics simulation approaches to resolve the mechanisms of cocrystal dissolution and precipitation. It was found that adsorption of the polymers on the surfaces of cocrystals might prevent the precipitation of the parent drug and alter the dissolution rate. The effect of polymers on precipitation could be determined by the cocrystal dissolution rate, the interactions of polymers with the surfaces of cocrystals, the characters of the noncovalent bonds formed between the polymers and the cocrystal surfaces, and the mobility and conformation of the polymers. The etching experiments of single cocrystals revealed that FFA-NIC and CBZ-NIC appeared as surface precipitation cocrystals while FFA-TP could lead to bulk precipitation. Both PVP and PVP-VA were good precipitation inhibitors for FFA-NIC, and they could completely inhibit the recrystallization of FFA III on the surfaces of dissolving cocrystals. In addition, as the adsorption of the polymer was slower than dissolution rate of the cocrystals, PVP and PVP-VA could only partially inhibit the recrystallization of CBZ dihydrate on the surface of CBZ-NIC. While PEG had no inhibitory effect on the surface crystallization of FFA-NIC and CBZ-NIC, due to its weak interactions with the surfaces of the cocrystals, it enhanced the dissolution performance of FFA-TP. In contrast, PVP and PVP-VA reduced the dissolution rate of FFA-TP and subsequently undermined the performance of cocrystals. Taken together, the approach of combining experimental and molecular dynamics simulation provided insights into the mechanisms of cocrystal dissolution as well as the polymers acting as inhibitory excipients for precipitation/recrystallization, making contribution to the development of novel formulations.

Curcumin-nicotinamide cocrystallization with supercritical solvent (CSS): Synthesis, characterization and in vivo antinociceptive and anti-inflammatory activities

Curcumin is a bioactive polyphenol, which presents several medicinal benefits such as antinociceptive, anti-inflammatory, anti-carcinogenic, antimalarial, and antioxidant activity. Despite the benefits, the main barrier in curcumin use by pharmaceutical industry is its low solubility in water medium and hence low bioavailability. The cocrystallization process is characterized by the incidence of molecular interactions between the active pharmaceutical ingredient and coformer that enables improvements in physicochemical properties such as solubility and bioavailability. The main objective of this work is to produce a curcumin-nicotinamide cocrystal by Cocrystallization with Supercritical Solvent (CSS) technique in order to increase curcumin water dissolution rate as well as antinociceptive/anti-inflammatory activities. Curcumin-nicotinamide cocrystal dissolution rate were about 2 times greater than pure curcumin in water medium. The cocrystallization process increased curcumin antinociceptive/anti-inflammatory potency probably due to alterations in its bioavailability. These results open new possibilities of use for curcumin cocrystals in pharmaceutical industries.

Development and characterization of Irbesartan Co-Crystals

The aim of the work was to prepare co-crystals of irbesartan (IBS), a BCS Class II drug to enhance its aqueous solubility and bioavailability. The solvent evaporation method was used to prepare co-crystals by using different co-formers and varying the drug to co-former molar ratios. Succinic acid and benzoic acid co-crystals were formed with good physicochemical properties. The solid-state characterization of co-crystals was studied by FTIR, DSC, and XRD. The co-crystals were evaluated for the saturation solubility and dissolution studies. There was a 2-fold increase in the aqueous solubility and 4-8 fold increase in dissolution rate of co-crystals. Solid state characterizations indicated there was no change in the chemical nature of the co-crystals compared to pure drug. Presence of crystalline co-former induced crystallinity to the developed co-crystals. Thus, developed co-crystals were found to be a suitable alternative to increase the solubility and dissolution rate of IBS.

PREPARATION OF ACYCLOVIR-NICOTINAMIDE COCRYSTAL BY SOLVENT EVAPORATION TECHNIQUE WITH VARIATION OF SOLVENT

ABSTRACTObjective: This research aims to prepare cocrystal of acyclovir (ACV)-nicotinamide (NCT) by solvent evaporation with a variation of solvent (ethanol,glacial acetic acid, and HCl 0.1 N) to improve the bioavailability of ACV as an antiviral drug.Methods: Cocrystal were developed by solvent evaporation with 1:1 molar fraction, using variation of solvent such as ethanol, glacial acetic acid, andHCl 0.1 N. Further, the prepared ACV-NCT cocrystal were characterized for differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD),Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), and in vitro dissolution.Results: DSC thermogram showed that ACV-NCT cocrystal in ethanol and glacial acetic acid exhibited new endothermic peak at 221.16°C and216.40°C, whereas no peaks were found for HCl 0.1 N. PXRD diffractogram showed that ACV-NCT cocrystal in ethanol exhibited new diffraction peaksat 2θ 5.9°; 9.2°; dan 13.3°, whereas no peaks were found for glacial acetic acid and HCl 0.1 N. FT-IR characterization of ACV-NCT cocrystal in ethanolshowed disappearance of transmission peaks at 3373/cm indicating the loss of NH bands of NCT. Furthermore, C=O of ACV and NCT were observed at1693/cm, and 1666/cm indicated a formation of hydrogen bonding between ACV and NCT. SEM micrographs showed that cocrystals have a differentshape compared to ACV and NCT. DE15 showed that there was a significant increase of ACV-NCT cocrystal dissolution rate in ethanol compared to thephysical mixture and ACV.Conclusion: The study concludes that ACV-NCT cocrystal in ethanol were successfully formed and the dissolution rate of ACV can increase significantly(α=0.05).Keywords: Cocrystallization, Solvent, Acyclovir, Nicotinamide, Solvent evaporation.

Improvement of physicochemical parameters of acyclovir using cocrystallization approach

Acyclovir is an antiviral drug having potent activity against the virus of herpes family and varicella zoster. Unfortunately, drug suffers very poor oral bioavailability (15-30%). The main objective of present study was to develop acyclovir cocrystals with improved solubility which may result in improvement of bioavailability. Hansen solubility approach was used as a tool to predict the cocrystal formation of a drug with selected coformer. Cocrystals of acyclovir with various coformers were screened in order to enhance their water solubility. Cocrystals of the drug were prepared using various methods like solvent evaporation, wet grinding, and antisolvent addition. Formation of cocrystals by solvent evaporation method was found to be better method amongst all. Optimization of cocrystal formation was carried out by employing different solvents as well as the stoichiometric ratio of acyclovir with that of coformer. Synthesis of cocrystals was optimized using water as a solvent system resulted in good agreements. The potential cocrystal formation of acyclovir was characterized by IR, PXRD and DSC techniques. An in-vitro dissolution study was performed to determine the dissolution rate of cocrystals. The results suggest that acyclovir forms cocrystals with tartaric acid and the initial dissolution rate of synthesized cocrystals were considerably faster as compared to pure acyclovir.

Solubility and dissolution rate of a carbamazepine–cinnamic acid cocrystal

Synthesis of cocrystals is one of the methods to alter physicochemical properties of drugs. A cocrystal of carbamazepine (CBZ) and cinnamic acid (CIN) was synthesized using solvent evaporation and was characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). The kinetic solubility, powder dissolution rate and stability of CBZ in aqueous solution were compared with those of cocrystal form (CBZ–CIN). Quantification of CBZ was evaluated using a UV-spectrophotometric technique in the presence of CIN that their spectrums are highly overlapped. Therefore, a recently developed net analyte signal standard addition method (NASSAM) was applied for determination of CBZ in the presence of CIN. The PXRD, DSC and FT-IR studies confirm that the cocrystal formation between CBZ and CIN and the developed NASSAM method can be used to quantitative determination of CBZ concentration in presence of CIN. The powder dissolution rate of cocrystal of CBZ–CIN is higher than CBZ and the kinetic solubility study show that the cocrystal is stable in dissolution medium and the aqueous solubility of CBZ–CIN is higher than CBZ. These findings show that formation of CBZ–CIN cocrystal is a suitable method to increase dissolution rate and solubility of CBZ and NASSAM is a valuable analytical method to quantitative determination of drugs in the presence of coformer in cocrystal studies.