Powder X-ray diffraction method for the quantification of cocrystals in the crystallization mixture

Context: The solid state purity of cocrystals critically affects their performance. Thus, it is important to accurately quantify the purity of cocrystals in the final crystallization product.

Objective: The aim of this study was to develop a powder X-ray diffraction (PXRD) quantification method for investigating the purity of cocrystals. The method developed was employed to study the formation of indomethacin-saccharin (IND-SAC) cocrystals by mechanochemical methods.

Materials and methods: Pure IND-SAC cocrystals were geometrically mixed with 1:1 w/w mixture of indomethacin/saccharin in various proportions. An accurately measured amount (550?mg) of the mixture was used for the PXRD measurements. The most intense, non-overlapping, characteristic diffraction peak of IND-SAC was used to construct the calibration curve in the range 0–100% (w/w). This calibration model was validated and used to monitor the formation of IND-SAC cocrystals by liquid-assisted grinding (LAG).

Results: The IND-SAC cocrystal calibration curve showed excellent linearity (R²?=?0.9996) over the entire concentration range, displaying limit of detection (LOD) and limit of quantification (LOQ) values of 1.23% (w/w) and 3.74% (w/w), respectively. Validation results showed excellent correlations between actual and predicted concentrations of IND-SAC cocrystals (R²?=?0.9981).

Discussion: The accuracy and reliability of the PXRD quantification method depend on the methods of sample preparation and handling. The crystallinity of the IND-SAC cocrystals was higher when larger amounts of methanol were used in the LAG method.

Conclusion: The PXRD quantification method is suitable and reliable for verifying the purity of cocrystals in the final crystallization product.     

Comparison of the relative stability of pharmaceutical cocrystals consisting of paracetamol and dicarboxylic acids

Objective: The aim of this study is to evaluate the relative stability of pharmaceutical cocrystals consisting of paracetamol (APAP) and oxalic acid (OXA) or maleic acid (MLA).

Significance: These observations of cocrystal stability under various conditions are useful coformer criteria when cocrystals are selected as the active pharmaceutical ingredient in drug development.

Method: The relative stability was determined from the preferentially formed cocrystals under various conditions.

Result: Cocrystal of APAP–OXA was more stable than that of APAP–MLA in a ternary cogrinding system and possessed thermodynamical stability. On the other hand, when grinding with moisture or maintaining at high temperatures and relative humidity conditions, APAP–MLA was more stable, and OXA converted to OXA dihydrate. In the slurry method, APAP–OXA was more stable in aprotic solvents because the APAP–OXA with low-solubility product precipitated.

Conclusions: The relative stability order was affected by preparing conditions of presence of moisture. This order might attribute to the small difference of crystal structure in the extension of the hydrogen bond network.     

Evaluation of performance of co crystals of mefloquine hydrochloride in tablet dosage form

Objective: The objective of present investigation was to evaluate performance of cocrystals of Mefloquine Hydrochloride (MFL) in tablet dosage form. Our previous investigation showed significant effect of cocrystal formers on improving the solubility and dissolution rate of Mefloquine hydrochloride by cocrystallization method when prepared by solution cocrystallization method.

Materials and methods: Prepared cocrystals of MFL with different ratio of cocrystal formers were incorporated in tablet dosage form and evaluated for micrometric properties, drug content, hardness, disintegration test, vitro dissolution studies and stability studies. Performance was compared with laboratory prepared tablet of MFL 250 mg.

Results: The considerable improvement in the dissolution rate was observed in case of cocrystals based tablets than pure MFL tablets.

Discussion and conclusion: So we can incorporate cocrystals in tablet dosage form to enhance in vitro and in vivo performance. To the best of our knowledge, this is the first report, cocrystals has been evaluated in tablet dosage form.     

Appropriate selection of an aggregation inhibitor of fine particles used for inhalation prepared by emulsion solvent diffusion

Abstract

Context: Dry powder inhaler (DPI) formulations have been developed to deliver large amounts of drugs to the lungs.

Objective: Fine particles of a poorly water-soluble drug, the model drug ONO-2921, were prepared by the emulsion solvent diffusion (ESD) method for use in a DPI.

Methods: The effects of additives on the fine particle formation of ONO-2921 were estimated when droplets of an ethanolic drug solution were dispersed into aqueous media containing various additives. Subsequently, the suspensions were freeze-dried to create powdered samples to estimate the inhalation properties using a twin impinger and an Andersen cascade impactor.

Results: This simple ESD method produced submicron-sized ONO-2921 particles (approximately 600?nm) in combination with suitable additives. In addition, the freeze-dried powder produced using additives exhibited superior in vitro inhalation properties. Among these methods, the freeze-dried powder produced with 0.50% weight/volume one type of polyvinyl alcohol (PVA-205) displayed the most efficient features in the fine particle fraction (FPF). These results could be explained by the stabilization of the ONO-2921 suspension by PVA-205, indicating that PVA-205 acts as an aggregation inhibitor of fine particles.

Conclusions: The ESD method, in combination with appropriate types and amounts of additives, may be useful for preparing a DPI suitable for delivering drugs directly to the lungs without the assistance of carrier particles.     

Multicomponent crystals of gliclazide and tromethamine: preparation,physico-chemical,and pharmaceutical characterization*

Objective: To improve the pharmaceutical behavior of the oral antidiabetic agent gliclazide through the synthesis of multicomponent crystals with tromethamine.

Methods: Multicomponent crystals were prepared by solvent evaporation method, kneading, and combining mechanical and thermal activation. DSC, FT-IR spectroscopy, X-ray diffraction, SEM-EDS, and SSNMR were used to investigate their formation. Measurements of solubility and dissolution rate were carried out for the pharmaceutical characterization.

Results: The formation of multicomponent crystals of gliclazide and tromethamine was confirmed by all the techniques. In particular, FT-IR and NMR measurements revealed that the interaction between drug and coformer leads to significant changes of the hydrogen bond scheme, and that almost all the functional groups of the two molecules are involved. The dissolution profile of the new phase is significantly better than that of both pure gliclazide and of the reference commercial product Diabrezide^®.

Conclusions: The new system shows an improved pharmaceutical behavior and could be formulated in a dosage form to obtain a rapid and complete release of the drug available for absorption.     

Dissolution Characteristics of Interactive Powder Mixtures. Part One: Effect of Solubility and Particle Size of Excipients

Abstract

Interactive mixtures of fine cohesive drug powders and coarse free flowing excipients are reported to increase dissolution rates of poorly soluble drugs. However, dissolution rates are known to be affected by the solubility characteristics of the excipients as well as excipients surface characteristics after mixing with lubricant.

In this study the effects of solubility and particle size of excipients on dissolution of micronized griseofulvin from interactive powder mixtures were investigated. Quantitative assessment of dissolution from such mixtures showed that systems containing soluble excipients increased dissolution of the drug more efficiently than mixtures prepared using insoluble excipients. The role of the soluble excipient was more significant after mixing with magnesium stearate. Excipients of smaller particle sizes increased dissolution more efficiently than their large size counterparts. Effects of particle size were particularly significant in case of water insoluble excipients.     

Dry powders for the inhalation of ciprofloxacin or levofloxacin combined with a mucolytic agent for cystic fibrosis patients

Objective: This study aimed to design and characterize an inhalable dry powder of ciprofloxacin or levofloxacin combined with the mucolytics acetylcysteine and dornase alfa for the management of pulmonary infections in patients with cystic fibrosis.

Methods: Ball milling, homogenization in isopropyl alcohol and spray drying processes were used to prepare dry powders for inhalation. Physico-chemical characteristics of the dry powders were assessed via thermogravimetric analysis, differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FT-IR), X-ray diffractometry and scanning electron microscopy. The particle size distribution, dissolution rate and permeability across Calu-3 cell monolayers were analyzed. The aerodynamic parameters of dry powders were determined using the Andersen cascade impactor (ACI).

Results: After the micronization process, the particle sizes of the raw materials significantly decreased. X-ray and DSC results indicated that although ciprofloxacin showed no changes in its crystal structure, the structure of levofloxacin became amorphous after the micronization process. FT-IR spectra exhibited the characteristic peaks for ciprofloxacin and levofloxacin in all formulations. The dissolution rates of micro-homogenized and spray-dried ciprofloxacin were higher than that of untreated ciprofloxacin. ACI results showed that all formulations had a mass median aerodynamic diameter less than 5?μm; however, levofloxacin microparticles showed higher respirability than ciprofloxacin powders did. The permeability of levofloxacin was higher than those of the ciprofloxacin formulations.

Conclusion: Together, our study showed that these methods could suitably characterize antibiotic and mucolytic-containing dry powder inhalers.     

Crystal engineering to improve physicochemical properties of mefloquine hydrochloride

Background: Pharmaceutical cocrystallization is a promising alternative for improving the solubility and dissolution rate or manipulating other physical properties of active pharmaceutical ingredients. The objective of this investigation was to study the effect of cocrystallization with different cocrystal formers on physicochemical properties of mefloquine hydrochloride. Method: Cocrystals were prepared by solution crystallization method – mefloquine hydrochloride (414.8 mg, 1 mmol) and different cocrystal formers (1/2 mmol) were dissolved in 20 mL of ethanol with warming. Solution was cooled in ice bath for 6 hours. The crystals were isolated by filtration through a membrane (0.45 μm) and dried in the air. The pure drug and the prepared cocrystals were characterized in terms of saturation solubility, drug content, infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, in vitro dissolution studies, and stability studies. Results: The cocrystals showed enhanced solubility and dissolution rate. The cocrystals were found to be stable over the period of 6 months confirmed from stability studies. Conclusion: Cocrystals resist the conversion of anhydrous form of drug into its hydrate which is responsible for the drugs less solubility and dissolution rate.     

The use of optimazation techniques in pharmaceutical development

Abstract

The lecture uses selected examples to illustrate the use of mathematical methods to optimize drug dosage forms:

Elucidation of compatibility between active ingredient and excipients required in the preformulation phase by factorial design.

Calculation of maximum allowable mean of particle sizes for active ingredient and the sum of auxiliary materials to achieve a sufficient content uniformity by applying the Stange-Pool equation.

Application of surface response research for identification of the working point in an “innocuous area of landscape” for scaling ups, handing over to production, of trouble shooting by using central composite desing and in the case of multiple constraints doing computerized grid search.

Only mentioned and not described in detail will be the methods for pharmacokinetical optimization, necessary for the development of modified release formulations.

Of course not for every development it is mandatory to use surface response research to get the necessary quality. But it is worthwile to apply refgularly factorial design for compatibility studies to calculate the necessary particle sizes and to compare in vivo results with dissolution rate data.     

Co-crystallization for enhanced dissolution rate of bicalutamide: preparation and evaluation of rapidly disintegrating tablets

Objectives: Enhance the dissolution rate of bicalutamide via co-crystallization with sucralose (sweetener), with the aim to develop rapidly disintegrating tablets with subsequent prompt dissolution.

Significance: Bicalutamide is antiandrogenic agent for the treatment of prostate cancer but has low and variable oral bioavailability, mainly attributed to poor dissolution. Co-crystallization with benign excipients is promising for dissolution enhancement with the additive serving dual functions. The benefit will become greater if dissolution enhancement is associated with the development of orodispersible tablets which is suitable for elderly patients who are the most vulnerable for prostate cancer.

Methods: Bicalutamide was dissolved in acetone in the presence of increasing molar ratios of sucralose. The solvent was evaporated while mixing to deposit crystals that were subjected to wet co-grinding until drying. The developed solids were characterized using Fourier transform infrared spectroscopy, differential thermal analysis and X-ray diffraction in addition to monitoring bicalutamide dissolution.

Results: Instrumental analysis provided evidences for co-crystallization which was initiated at 1:1 molar ratio of bicalutamide to sucralose with complete co-crystallization at 1:4 molar ratio. The co-crystals provided faster bicalutamide dissolution compared with the unprocessed drug and that recrystalized from acetone in the absence of sucralose. The formulation containing bicalutamide with sucralose at 1:4 molar ratio was selected for tablet formulation into which superdisintegrants were included. The developed tablets exhibited flash disintegration with subsequent fast dissolution of bicalutamide.

Conclusions: The study introduced co-crystallization of bicalutamide with sucralose as an efficient tool to enhance the dissolution rate and to develop rapidly dissolving tablets for intraoral administration.     

The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance

Abstract

The use of soluble cocrystal for delivering drugs with low solubility, although a potentially effective approach, often suffers the problem of rapid disproportionation during dissolution, which negates the solubility advantages offered by the cocrystal. This necessitates their robust stabilization in order for successful use in a tablet dosage form. The cocrystal between carbamezepine and succinic acid (CBZ-SUC) exhibits a higher aqueous solubility than its dihydrate, which is the stable form of CBZ in water. Using this model system, we demonstrate an efficient and material-sparing tablet formulation screening approach enabled by intrinsic dissolution rate measurements. Three tablet formulations capable of stabilizing the cocrystal both under accelerated condition of 40?°C and 75% RH and during dissolution were developed using three different polymers, Soluplus® (F₁), Kollidon VA/64 (F₂) and Hydroxypropyl methyl cellulose acetate succinate (F₃). When compared to a marketed product, Epitol® 200?mg tablets (F₀), drug release after 60?min from formulations F₁ (～82%), F₂ (～95%) and F₃ (～95%) was all higher than that from Epitol® (79%) in a modified simulated intestinal fluid. Studies in albino rabbits show correspondingly better bioavailability of F₁–F₃ than Epitol.     

Solid state manipulation of lornoxicam for cocrystals – physicochemical characterization

Context: Lornoxicam is an analgesic and anti-inflammatory drug of choice and belongs to Class II (low solubility) of BCS (Biopharmaceutical Classification System). Thus bioavailabilities problems are predominant.

Objective: Through crystal engineering approach, a method was developed for obtaining multi-component cocrystals of lornoxicam using pharmaceutically acceptable compounds as guests.

Materials and methods: Lornoxicam guest-free form was obtained from solution crystallization. Supramolecular synthon approach indicated that lornoxicam was in orthorhombic form. Further presence of intermolecular hydrogen bonding with layered structures was identified. Solvent drop grinding method permitted the formation of cocrystals of lornoxicam with catechol, resorcinol, benzoic acid, hydroxyquinone and 2,4 dihydroxy benzoic acid, all are capable of forming hydrogen bonding.

Results and discussion: Lornoxicam cocrystals exhibited the difference in melting points and decomposition characteristics. The analysis of infrared (IR) indicated the shifting of characteristic bands of lornoxicam. The XPRD (X-Ray Powder Diffraction) pattern indicated the crystallinity of cocrystals and significant difference in 2θ value of intense peaks. Differential scanning calorimetry spectra of cocrystals denoted the changes in fusion endotherms, which are in agreements with melting points. The pH solubility profile of lornoxicam showed sigmoidal curve, which substantiated the pK_a-dependent solubility. Lornoxicam cocrystals also exhibited a similar pH-solubility profile. Thus pairing of lornoxicam and coformers in the solution at high pH media was assumed. The in vitro dissolution studies of cocrystals were conducted at pH 4.0. The rapid rate of dissolution of cocrystals was observed in initial 10?min. The extent of dissolution was enhanced by 20% on account of cocrystallization.

Conclusion: The lornoxicam cocrystals were obtained with improved physicochemical characteristics.     

Investigation on Process Parameters Involved in Polylactide-Co-Glycolide Microspheres Preparation

Abstract

Indomethacin loaded polylactide-co-glycolide (PLGA) microspheres were prepared by emulsification solvent evaporation. The preparation involves several process parameters that can affect the morphological characteristics, the “in vitro” and “in vivo” dissolution behaviour of microspheres.

The evaluation of three process parameters, emulsification stirring rate, emulsifier concentration and dispersed phase to continuous phase ratio was carried out in order to correlate them to some microsphere properties.

Results show that the variables evaluated affect mainly microspheres drug content and, at less extent, particle size.     

Comparison of the Solubility and Dissolution Rate Between Gliclazide Solid Complex and Its Nanospheres

ABSTRACT

The solid complex of gliclazide and β-cyclodextrin was prepared by neutralization method and the precipitation solvent evaporation method was used to prepare gliclazide nanospheres. Fourier-transform infrared spectroscopy and differential scanning calorimetry were used to examine whether gliclazide solid complex and gliclazide nanospheres were successfully formed in this study. The dissolution rate of gliclazide from its nanospheres was faster than its solid complex and pure drug. The morphology of particles for nanospheres showed no crystal character of gliclazide. In summary, the results indicate that nanotechnology provides better effects in solubility and dissolution rate of gliclazide than neutralization method.     

Gastrointestinal stability,physicochemical characterization and oral bioavailability of chitosan or its derivative-modified solid lipid nanoparticles loading docetaxel

Abstract

Objective: The purpose of this study was to prepare the positively charged chitosan (CS)- or hydroxypropyl trimethyl ammonium chloride chitosan (HACC)-modified solid lipid nanoparticles (SLNs) loading docetaxel (DTX), and to evaluate their properties in vitro and in vivo.

Methods: The DTX-loaded SLNs (DTX-SLNs) were prepared through an emulsion solvent evaporation method and further modified with CS or HACC (CS-DTX-SLNs or HACC-DTX-SLNs) via noncovalent interactions. The gastrointestinal (GI) stability, dissolution rate, physicochemical properties and cytotoxicities of SLNs were investigated. In addition, the GI mucosa irritation and oral bioavailability of SLNs were also evaluated in rats.

Results: The HACC-DTX-SLNs were highly stable in simulated gastric and intestinal fluids (SGF and SIF). By contrast, the CS-DTX-SLNs were less stable in SIF than in SGF. The drug dissolution remarkably increased when DTX was incorporated into the SLNs, which may be attributed to the change in the crystallinity of DTX and some molecular interactions that occurred between DTX and the carriers. The SLNs showed low toxicity in Caco-2 cells and no GI mucosa irritations were observed in rats. A 2.45-fold increase in the area under the curve of DTX was found in the HACC-DTX-SLN group compared with the DTX group after the modified SLNs were orally administered to rats. However, the oral absorption of DTX-SLN or CS-DTX-SLN group showed no significant difference compared with that of DTX group.

Conclusions: The positively charged HACC-DTX-SLNs with a stable particle size could provide the enhanced oral bioavailability of DTX in rats.     

Novel approach to control CdS morphology by simple microwave-solvothermal method

Nanosize CdS powders with different microstructures are prepared in different solvents by using rapid microwave irradiation. Effect of solvents and Cd²⁺ precursors are to be able to control the particle size, and microstructures of CdS have been investigated by X-ray diffraction and TEM. The different particle size and morphologies are observed using different Cd²⁺ precursors in different solvents. TEM micrographs clearly show multiarmed nanorods and spherical shape morphologies of CdS powders are obtained in polar solvent like water (H₂O), whereas non-polar polyol solvent like ethylene glycol (EG), prickle and cluster like morphologies of CdS are achieved with different Cd²⁺ precursors such as CdSO₄ and Cd (CH₃COO)₂. The spectroscopy studies of nanosize CdS are examined by photo-luminescence spectra. Band gap and the absorption co-efficient for nano CdS is also evaluated from optical absorption studies.     

Tunable morphology and magnetic properties of Bi2Fe4O9 nanocrystal synthesized by hydrothermal method

Bi2Fe4O9 nano and micron powders have been synthesized by a hydrothermal method. The as-obtained samples are pure phase and crystallize in the orthorhombic structure. Diverse particle morphologies, including nanoplates, nanospheres, microcubes, and microcylinders, are obtained under different synthesis conditions. The solvent N,N-Dimethylformamide (DMF), together with the mineralisers NaOH and NH4OH, are found to be the key factors for the formation of the particles with their diverse morphologies and sizes. The magnetization dependence of temperature (M-T), observed in a field of 1000 Oe from 10 to 340 K, and M-H loops measured at 10 K indicate that the Bi2Fe4O9 particles are paramagnetic at room temperature and undergo an antiferromagnetic transition at a Néel temperature (T(N)) of 250 K.     

A Comparison of the Properties of Some Chloramphenicol and Neomycin Eye Ointments,Commercially Available in the U.K

Abstract

The rheology, particle size distribution and drug release, measured by dissolution and agar diffusion techniques, of five B.P. Chloramphenicol Eye Ointments and three B.P. Neomycin Eye Ointments have been examined. All ointments showed structural breakdown during continuous shear rheology. Three chloramphenicol ointments displayed spur values whilst one neomycin ointment displayed a bulge on the up-curve of the rheogram. Mass median particle sizes ranged from 6.0 to 13.0 and 5.4 to 9.6 μm for the chloramphenicol and neomycin ointments respectively. Drug release similarly varied. By dissolution techniques the quantity of chloramphenicol that dissolved in 60 minutes ranged from 22 to 41 μg whilst agar diffusion studies produced drug releases which varied from 2.4 to 4.7 and 0.8 to 2.3 μg for the chloramphenicol and neomycin results respectively.     

Effect of Particle Size on the Dissolution Rate of Monophenylbutazone Solid Dispersion in Presence of Certain Additives

Abstract

Monophenylbutazone is a very sparingly soluble drug. The effect of particle size on the dissolution characteristics of monophenylbutazone in a dissolution medium of 0.1 N hydrochloric acid and 0.1 N hydrochloric acid to which was added 0.005% Tween 80, was carried out. The enhancement of the dissolution rate of the medicament was attained by formulating the drug in both solid dispersion and physical mixture using urea and polyethylene glycol 4000 as carriers. A comparative dissolution behaviour of the medicament in different solid dispersion and physical mixture ratios were investigated at particle, size of < 63 μ. Drug-urea solid dispersion of a ratio 5:95% produced the highest dissolution rate.