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The aim of present work was to improve physicochemical properties of model drug Chlorzoxazone by crystallo-co-agglomeration (CCA) in the presence of different polymers and excipients. Identification of Quality Target Product Profile and Critical Quality Attributes were done using Risk assessment and Failure mode effect analysis. CCA was formulated by applying Box–Behnken design followed by principal component analysis (PCA). CCA was further studied for its topographical, micromeritic, mechanical, compressional, and dissolution properties. Prepared CCA showed improvement in flow and packability with rich drug content (90.84%). Heckel parameters indicated greater plastic deformation (K = 0.8132) and tensile strength compared to the pure drug (K = 19.256 kg/cm2). CCA showed negligible elastic recovery (0.87%) compared to the pure drug (5.708%). Dissolution of the drug was increased to 2.69-folds compared to the pure drug after 60 min. No degradation or polymorphic transformation of the drug was observed even after stability study (40 °C, 75% RH). The amount of directly compressible diluents could be minimized in tablet formulation, which was a considerable improvement in the properties of the drug for making directly compressible form. The study highlights an improvement of processing characteristics of Chlorzoxazone by CCA using an integrated approach of QbD and PCA. [ABSTRACT FROM AUTHOR]

Crystallo-co-agglomeration (CCA) is an innovative technique developed with the intention to produce the drugs with good micromeritic and mechanical characteristics. Atazanavir sulphate is an anti-retroviral drug with poor dissolution and poor flow properties. Hence the aim of the study is to prepare the crystallo coagglomerates of atazanavir sulphate which may improve the properties of atazanavir sulphate. The present study was carried out in order to develop pharmaceutically equivalent, stable, and quality improved agglomerates of atazanavir sulphate with enhanced solubility wettability, dissolution rate, flow properties and mechanical properties using hydrophilic polymers and to characterize the physico-chemical properties of prepared crystallo-co-agglomeration. The present work was carried out using PVA and PEG 6000 as the polymers in different ratios by crystallo-co agglomeration method. The various evaluations of prepared agglomerates like micromeritics of the agglomerates such as flowability, packability and compatibility were dramatically improved. The dissolution and disintegration rate of agglomerate was increased in presence of PEG 6000 than compared with PVA. The atazanavir sulphate polymer agglomerates were successfully prepared by crystallo-co-agglomeration technique and it was concluded that crystallo-co-agglomeration technique can be successfully employed as an alternative to conventional wet agglomeration. [ABSTRACT FROM AUTHOR]

A target of best dissolution improvement of poorly soluble drugs is a necessity for the success of formulation in industry. The present work describes the preparation, optimization, and evaluation of a new spherical agglomeration technique for glimepiride as a model of poorly soluble drugs. It involved the emulsification of a drug solution containing a dispersed carrier that tailors the crystal habit of the drug to a perfect spherical geometry, in a poor solvent containing a hydrophilic polymer which imparts sphericity and strength to the formed agglomerates. The FTIR peaks of optimized product did not show any sign of chemical interaction between the drug and adsorbed carrier. The DSC and X ray diffractogram showed a peak characteristic of spherical agglomerates with much less intensity than that of glimepiride. The dissolution t1/2 of the drug slightly decreased from 381 min to 334 min in plain agglomerates. Introducing polymers in the aqueous phase of emulsion led to an improvement in the dissolution, reflected in t1/2 ranging from 118 to 231 min. Agglomerates prepared with Starlac/PVP demonstrated the most optimum physicochemical characteristics being spherical, with the best flowability and packability parameters. The t1/2 was as short as 19 min. The new carrier/polymer system offered a synergistic combination that highly contributed in dissolution enhancement of glimepiride. The spheronization and amorphisation offered by the new technique could account for such improvement. [ABSTRACT FROM AUTHOR]

Crystallo-co-agglomeration is a novel particle design technique, to overcome the limitations of spherical crystallization. The process of Crystallo-co-agglomeration involves crystallization followed by simultaneous agglomeration of the drug with the aid of either a good solvent or a bridging liquid and a bad solvent. The agglomeration is performed using bridging liquid. In the field of powder technology various attempts has been made to design primary and secondary particles of pharmaceutical substances for various applications, such as improvement in solubility of drugs, obtaining suitable polymorph, improvement in micromeritics and compression properties, and modification of bioavailability. [ABSTRACT FROM AUTHOR]

Objectives: The aim of the present study was to obtain CCA of ritonavir to improve the solubility, dissolution rate, and other physicochemical properties. Materials and Methods: Ritonavir agglomerates were prepared using the CCA technique. Acetone-water containing HPMC K-15, PEG-6000, PVP K-30 was used as the crystallization medium. The agglomerates were evaluated for saturation solubility, micromeritic properties, yield, and drug content. The agglomerates were also characterized using FTIR, DSC, XRPD and SEM. Results: The growth of particle size and the spherical form of the agglomerates resulted in the formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to the fragmentation that occurred during compression. DSC and XRD studies showed that ritonavir particles crystallized in the presence of HPMC, PEG-6000, PVP K-30 and diluents did not undergo structural modifications. The solubility and dissolution rate of ritonavir agglomerates were improve compare to pure ritonavir. Conclusion: CCA was successfully applied to improve the physicochemical properties of ritonavir. [ABSTRACT FROM AUTHOR]

The purpose of this research work was to obtain directly compressible agglomerates of Artemether using a Crystallo-co-agglomeration technique. Crystallo-co-agglomeration is an extension of the spherical crystallization technique, which enables simultaneous crystallization and agglomeration of two or more drugs or excipients. Here Acetone-water system containing PEG 6000, and HPMC K100M was used in crystallization system. Acetone acted as a good solvent and Distilled water act as bad solvent for Artemether and Dichloromethane acted as a bridging liquid for agglomeration. The agglomerates were evaluated for micromeritic properties, surface morphology, solubility, compressibility, and in vitro dissolution study. The compatibility study was done by FTIR and Surface morphology was done by optical microscopy. The result revealed that micromeritic properties observed enabled direct compression without any defect. The FTIR study revealed the compatibility among the drug and excipients.in vitro dissolution study revealed that as the polymer concentration changes, drug release also changes. From this study, it is concluded that Crystallo-co-agglomeration technique is a suitable alternative method to the granulation process and can be used for design of sustained release Artemether agglomerates with varying concentration of polymer. [ABSTRACT FROM AUTHOR]

Pharmaceutical tablets are a popular solid dosage form and have a significant ratio in the available solid dosage forms. They are a popular choice for patients due to the ease of administration as well as for pharmaceutical manufacturers due to the low cost of manufacturing, packaging, and other pharmaceutical parameters. However, the drug powder should either be crystalline or turned into a granular form using wet-dry granulation techniques to improve the flow and compressibility. The valsartan drug, which is commonly used as an antihypertensive drug, is an amorphous drug and has an angle of repose of more than 40º. Therefore, it needs to be converted into a granular form. This work uses the spherical crystals of the valsartan drug because they flow well and can be used for pharmaceutical tablets. Different process parameters, such as mixing speed, mixing time, and temperature, were optimized to obtain effective process parameters. The final batch of spherical crystals of valsartan had an angle of repose of 27.23º, which shows that prepared spherical crystals flow well., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Gupta et al.)

Abstract: This research presents the use of experimental design, optimization and multivariate techniques to investigate the root-cause of agglomerates containing two drugs [i.e. racecadotril (RCD) and loperamide hydrochloride (LPM)]. The influence of various excipients and processing conditions on formation of directly compressible agglomerates was prepared by crystallo-co-agglomeration (CCA) technique and evaluated. Design of experimental (DoE) was carried out to evaluate the interactions and effects of the design factors on critical quality attributes (CQAs) of agglomerates. The design space was studied by DoE and multivariate analysis to ensure desired physico-chemical properties of agglomerates. The overall higher yield of the process with sufficient size of agglomerates was prepared by CCA. The optimized agglomerates exhibited excellent flowability and crushing strength along with good compressibility and compactibility. The optimized batch of agglomerates was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffractometry and gas chromatography which illustrated the absence of drug–excipient interaction with minimal entrapment of solvent. It was demonstrated that QbD principles and tools provide an effective means to achieve a greater understanding of agglomerates prepared by CCA which adopted as an excellent alternative to wet granulation. [Copyright &y& Elsevier]

Highlights: [•] We employed CCA to develop directly compressible racecadotril agglomerates. [•] We implemented PCA with AHCA to determined similarity amongst all batches. [•] Agglomerates possessed good compressibility hence were suitable for direct tableting. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the present investigation was to improve the flow and mechanical properties of racecadotril by a crystallo-co-agglomeration (CCA) technique. Direct tableting is a requirement of pharmaceutical industries. Poor mechanical properties of crystalline drug particles require wet granulation which is uneconomical, laborious, and tedious. Materials and Methods: The objective of this work was to study the influence of various polymers/excipients and processing conditions on the formation of directly compressible agglomerates of the water-insoluble drug, racecadotril, an antidiarrheal agent. The agglomerates of racecadotril were prepared using dichloromethane (DCM)--water as the crystallization system. DCM acted as a good solvent for racecadotril as well as a bridging liquid for the agglomeration of the crystallized drug and water as the nonsolvent. The prepared agglomerates were tested for micromeritic and mechanical properties. Results: The process yielded ~90 to 96% wt/ wt spherical agglomerates containing racecadotril with the diameter between 299 and 521 μ. A higher rotational speed of crystallization system reduces the size of the agglomerates and disturbs the sphericity. Spherical agglomerates were generated with a uniform dispersion of the crystallized drug. CCA showed excellent flowability and crushing strength. Conclusion: Excipients and processing conditions can play a key role in preparing spherical agglomerates of racecadotril by CCA, an excellent alternative to the wet granulation process to prepare intermediates for direct compression. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of the present research was to obtain directly compactible agglomerates of naproxen containing disintegrant by a novel crystallo-co-agglomeration (CCA) technique. Acetone–water containing hydroxypropylcellulose (HPC) was used as the crystallization medium. Acetone acted as a good solvent for naproxen as well as a bridging liquid for agglomeration of crystallized drug with disintegrant and aqueous phase as non-solvent. The agglomerates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD) and scanning electron microscopy. The agglomerates were compressed at different compression pressures and dissolution studies were carried out for the tablets produced at lowest compression force. The growth of particle size and the spherical form of the agglomerates resulted in formation of products with good flow and packing properties. The improved compaction properties of the agglomerated crystals were due to the fragmentation which occurred during compression. DSC and XRPD studies showed that naproxen particles, crystallized in the presence of HPC and disintegrant did not undergo structural modifications. The dissolution rate of naproxen from the agglomerates could be controlled by the amount of included disintegrant, being enhanced as the latter was increased. Moreover, the results showed that when the disintegrants were included both intragranularly and extragranularly during agglomeration of naproxen particles, tablets containing these agglomerates dissolved at a faster rate than the tablets containing crystallized naproxen with the same amount of disintegrant incorporated only extragranularly by physical mixing. In conclusion, the properties of agglomerated crystals, such as flowability, compactibility and dissolution rate were improved profoundly using the developed technique resulting in successful direct tableting without need to additional process of physical blending of agglomerates and disintegrants. [Copyright &y& Elsevier]

The purpose of this research was to study the effect of concentration of polyethylene glycol and ethyl cellulose on the properties of agglomerates of ibuprofen-paracetamol obtained by crystallo-co-agglomeration technique. The process of crystallo-co-agglomeration involved recrystallization of ibuprofen and its simultaneous agglomeration with paracetamol in presence polymers. The effect of combination of polyethylene glycol and ethylcellulose was studied by 22 factorial design. Ibuprofen content of the agglomerate increased with increase in ethyl cellulose while paracetamol content was decreased with increase in polyethylene glycol. Differential scanning calorimetry thermograms of agglomerates showed the unchanged endotherm for ibuprofen melting, whereas paracetamol endotherm was diffused with low enthalpy. The agglomerates were spherical but increase in polyethylene glycol caused its deformation. Agglomerates containing ethylcellulose with polyethylene glycol have higher resistance for fragmentation, modulus of elasticity but impart high tensile strength. [ABSTRACT FROM AUTHOR]

The purpose of this research work was to obtain directly compressible agglomerates of ibuprofen with talc by a novel crystallo-co-agglomeration (CCA) technique, which is an extension of spherical crystallization. Ibuprofen-talc agglomerates were prepared using dichloromethane (DCM)-water as the crystallization system. DCM acted as a good solvent for ibuprofen as well as a bridging liquid for agglomeration of crystallized drug with talc. The agglomerates were characterized by differential scanning calorimetry, powder X-ray diffraction, and scanning electron microscopy and were evaluated for tableting properties and for drug release. The process yielded spherical agglomerates containing ∼95% to 96% wt/wt of ibuprofen. Agglomerates containing talc showed uniform distribution of hydroxypropylmethylcellulose and decreased crystallinity, and deformed under pressure. The miniscular form of ibuprofen and the hydrophobicity of talc governed the drug release rate. The batch containing a higher proportion of talc showed zeroorder kinetics and drug release was extended up to 13 hours. The CCA technique developed in this study is suitable for obtaining agglomerates of drug with talc as an excipient. [ABSTRACT FROM AUTHOR]

The purpose of this research was to obtain directly compressible agglomerates of ibuprofen-paracetamol containing a desired ratio of drugs using a crystallo-co-agglomeration technique. Crystallo-co-agglomeration is an extension of the spherical crystallization technique, which enables simultaneous crystallization and agglomeration of 2 or more drugs or crystallization of a drug and its simultaneous agglomeration with another drug or excipient. Dichloromethane (DCM)-water system containing polyethylene glycol (PEG) 6000, polyvinyl pyrollidone, and ethylcellulose was used as the crystallization system. DCM acted as a good solvent for ibuprofen and bridging liquid for agglomeration. The process was performed at pH 5, considering the low solubility of ibuprofen and the stability of paracetamol. Loss of paracetamol was reduced by maintaining a low process temperature and by the addition of dextrose as a solubility suppressant. The agglomerates were characterized by differential scanning calorimetry, powder x-ray diffraction (PXRD), and scanning electron microscopy and were evaluated for tableting properties. The spherical agglomerates contained an ibuprofen-paracetamol ratio in the range of 1.23 to 1.36. Micromeritic, mechanical, and compressional properties of the agglomerates were affected by incorporated polymer. The PXRD data showed reduction in intensities owing to dilution and reduced crystallinity. Thermal data showed interaction between components at higher temperature. Ethylcellulose imparted mechanical strength to the agglomerates as well as compacts. The agglomerates containing PEG have better comparessibility but drug release in the initial stages was affected owing to asperity melting, yielding harder compacts. The agglomeration and properties of agglomerates were influenced by the nature of polymer. [ABSTRACT FROM AUTHOR]