Spherical agglomeration to improve dissolution and micromeritic properties of an anticancer drug,Bicalutamide

Bicalutamide (BCT), an anticancer drug, suffers from dissolution rate limited bioavailability and poor micromeritic properties. Spherical crystallization involves the formation of spherical agglomerates with enhanced dissolution properties, obviating the need for further granulation process. The present investigation was focused on spherical agglomeration of BCT by quasi-emulsion solvent diffusion method. All the responses were subjected to principal component analysis to scrutinize the critical attributes. Further for optimization, X1; influence of phase ratio, X2; amount of PEG 6000 and X3; stirring speed on critical dependent variables was studied by employing the Box-Behnken experimental design. The agglomerates exhibited better flow properties, higher bulk density, and improved compressibility compared to pure powder drug. In-vitro release studies revealed enhancement of dissolution properties of poorly soluble BCT. Characterization studies carried out by differential scanning calorimeter and powder X-ray diffractometer revealed crystallinity of drug with decreased intensity in the formulation. Scanning electron microscopy showed spherical shape agglomerates of BCT. The residual solvents were largely below the permitted limits. Spherical agglomerates demonstrated enhanced dissolution properties on account of reduced particle size and partial conversion into amorphous form. Thus, spherical agglomerates of BCT seem to be a promising approach to ameliorate the dissolution properties which might thereby improve its bioavailability.     

Manipulation of Naproxen Particle Morphology Via the Spherical Crystallization Technique to Achieve A Directly Compressible Raw Material

Crystals of naproxen were modified by the spherical crystallization technique to improve the compression and flow characteristics of the drug substance. A naproxen:acetone solution was added to water, and the crystals were agglomerated with either hexanol, octanol, or toluene. The resulting agglomerates were compact spherical aggregates of plate shaped crystals, regardless of the agglomerating solvent used. The quantity of the agglomerating solvent and the temperature of the solvent system were critical process parameters, probably due to their effect on the drug solubilization. Crystal agglomeration sufficiently improved the intrinsic compressibility and flow characteristics of naproxen that the agglomerated material was directly compressible.     

Formulation studies on ibuprofen sodium–cationic dextran conjugate: effect on tableting and dissolution characteristics of ibuprofen

The effect of electrostatic interaction between ibuprofen sodium (IbS) and cationic diethylaminoethyl dextran (Ddex), on the tableting properties and ibuprofen release from the conjugate tablet was investigated. Ibuprofen exhibits poor flow, compaction (tableting) and dissolution behavior due to its hydrophobic structure, high cohesive, adhesive and viscoelastic properties therefore it was granulated with cationic Ddex to improve its compression and dissolution characteristics. Electrostatic interaction and hydrogen bonding between IbS and Ddex was confirmed with FT-IR and DSC results showed a stepwise endothermic solid–solid structural transformation from racemic to anhydrous forms between 120 and 175?°C which melted into liquid form at 208.15?°C. The broad and diffused DSC peaks of the conjugate granules as well as the disappearance of ibuprofen melting peak provided evidence for their highly amorphous state. It was evident that Ddex improved the flowability and densification of the granules and increased the mechanical and tensile strengths of the resulting tablets as the tensile strength increased from 0.67?±?0.0172 to 1.90?±?0.0038?MPa with increasing Ddex concentration. Both tapping and compression processes showed that the most prominent mechanism of densification were particle slippage, rearrangement and plastic deformation while fragmentation was minimized. Ddex retarded the extent of dissolution in general, indicating potentials for controlled release formulations. Multiple release mechanisms including diffusion; anomalous transport and super case II transport were noted. It was concluded that interaction between ibuprofen sodium and Ddex produced a novel formulation with improved flowability, tableting and dissolution characteristics with potential controlled drug release characteristics dictated by Ddex concentration.     

Manipulation of Naproxen Particle Morphology Via the Spherical Crystallization Technique to Achieve A Directly Compressible Raw Material

Abstract

Crystals of naproxen were modified by the spherical crystallization technique to improve the compression and flow characteristics of the drug substance. A naproxen:acetone solution was added to water, and the crystals were agglomerated with either hexanol, octanol, or toluene. The resulting agglomerates were compact spherical aggregates of plate shaped crystals, regardless of the agglomerating solvent used. The quantity of the agglomerating solvent and the temperature of the solvent system were critical process parameters, probably due to their effect on the drug solubilization. Crystal agglomeration sufficiently improved the intrinsic compressibility and flow characteristics of naproxen that the agglomerated material was directly compressible.     

Dissolution properties of direcet compression tablets containing an agglomerated cellulose powder

In previous studies a novel agglomerated cellulose powder was shown to own advantageous properties for direct compression. Due to the favourable particle and powder properties this material has good binding and disintegration ability in direct compression tablets. In this study the dissolution properties of direct compression tablets containing the agglomerated cellulose powder as a fillerbinder were evaluated. Especially the effect of the amount of cellulose, the porosity of tablets, the solubility of drug material and the amount and the amount and mixing method of lubricant, magnesium stearate were studied.

Tablets containing different amounts of cellulose with dicalcium phosphate as a filler and 10 wt % of water soluble sodium tolmetin as a drug were compressed at a constant pressure of 150 MPa. The breaking strength of tablets increased with increasing amounts of agglomerated cellulose powder. However, the dissolution of drug accelerated up to cellulose amount of 50 wt %. This was due to the ability of the agglomerated cellulose powder to enhance the water penetration into powder compact and the loosening of tablet structure, i.e. formation of cracks.

Tablets containing 20 wt % of cellulose material and 10 wt % of drug material were compressed to different porosities. Tablet porosity had no effect on dissolution of poorly water soluble tolfenamic acid. Also the dissolution of water soluble sodium tolmetin was only slightly affected by the porosity of tablets. This supports the suggested disintegrant mechanism of the agglomerated cellulose powder. The expansion of cellulose agglomerates, which have been deformed, under compression, is widely responsible for the disintegration of the tablets. An increase in the amount as well as in the mixing intensity of magncsium stearate decreased the dissolution of sodium tolmetin from tablets containing 20 wt % of agglomerated cellulose. However, the intrinsic wetting and dissolution phenomens were practically unchanged when the amount of magnesium stearate was below 2 wt %. Thus, the retardation of drug dissolution was acceptable at low lubricant concentrations.

The properties of tablets containing the agglomerated cellulose were compared to those containing microcrystalline cellulose. In all cases tablets containing the agglomerated cellulose powder liberated drug clearly faster and more properly than corresponding microcrystalline cellulose tablets.     

Properties of Ibuprofen Crystallized Under Various Conditions: A Comparative Study

ABSTRACT

Different crystal forms of the analgesic drug ibuprofen were prepared and characterized in this study. Various conditions were used for the crystallization: crystallization was carried out using the solvent change method, the temperature change method, and the solvent evaporation method. Crystals were grown from different solvents. Different crystal forms with different properties were observed: cubic, needle-shaped, and plate-shaped crystals were obtained. Spherical agglomeration occurs when crystallization is carried out in acetonitrile or methanol. Flowability of these spherical crystals is increased. All crystals were determined as isomorphic by differential scanning calorimetry and x-ray analysis—which queries doubtful results of recent publications. Properties like dissolution behavior and properties influencing the manufacturing of dosage forms—like flowability—differ. Thus the choice of the optimal preparation method influencing the crystal habit is important in manufacturing the drug ibuprofen.     

Properties of ibuprofen crystallized under various conditions: a comparative study

Different crystal forms of the analgesic drug ibuprofen were prepared and characterized in this study. Various conditions were used for the crystallization: crystallization was carried out using the solvent change method, the temperature change method, and the solvent evaporation method. Crystals were grown from different solvents. Different crystal forms with different properties were observed: cubic, needle-shaped, and plate-shaped crystals were obtained. Spherical agglomeration occurs when crystallization is carried out in acetonitrile or methanol. Flowability of these spherical crystals is increased. All crystals were determined as isomorphic by differential scanning calorimetry and x-ray analysis—which queries doubtful results of recent publications. Properties like dissolution behavior and properties influencing the manufacturing of dosage forms—like flowability—differ. Thus the choice of the optimal preparation method influencing the crystal habit is important in manufacturing the drug ibuprofen.     

Flowability of binary mixtures of commercial and reprocessed ibuprofen through high shear wet milling (HSWM) with lactose

This study investigates the flow properties of binary mixtures of both commercial ibuprofen and reprocessed ibuprofen through high shear milling with lactose powders. Ibuprofen is recrystallized in a 30% water–ethanol mixture before high shear wet milling (HSWM). In-situ Process Analytical Techniques (PAT) (Labmax®) is used to study the HSWM process dynamics, with particle size measured by a Lasentec Focused Beam Reflectance Measurement, FBRM®. The flow properties of the binary mixtures of the different ibuprofen particles and its binary mixtures with lactose were measured using a Schulze® RST-XS ring shear tester. Results show that the morphology of ibuprofen was changed from needle to hexagonal like crystals during recrystallization and crystal size was reduced dramatically by HSWM for 1 h. The flowability of milled ibuprofen powders is reduced significantly due to its reduced size and change of surface morphology. Mixing the HSWM ibuprofen powders with lactose enhanced its flow properties. However, the increase of the mixture flowability for HSWM ibuprofen is less significant in comparison to the binary mixtures of lactose with commercial ibuprofen.     

Ultrasound-assisted preparation of novel ibuprofen-loaded excipient with improved compression and dissolution properties

Context: Most of the active pharmaceutical ingredients (APIs) suffer from a drawback of poor aqueous solubility. In addition to the same, some APIs show poor tabletting behavior creating problems in formulation development. Crystal engineering can be an efficient tool in rectification of such problems associated with the APIs. Thus present work deals with crystallization of ibuprofen (a model drug) onto the surface of dicalcium phosphate (DCP) particles using different techniques.

Objective: The objective of the present work was to prepare ibuprofen-loaded DCP particles and further to analyze them for compressibility and dissolution behavior.

Materials and methods: Various crystallization techniques such as solvent evaporation (SE), melt crystallization (MC), melt sonocrystallization (MSC), antisolvent crystallization (AC), and antisolvent sonocrystallization (ASC) were screened for the preparation of ibuprofen-loaded DCP. Products obtained from different techniques were analyzed for physicochemical, micromeritic and compression properties.

Results and discussion: ASC technique was found to be suitable for preparing directly compressible ibuprofen-loaded DCP particles. The change in the crystal habit (needle to plate shape) of ibuprofen and its crystallization in miniscular form onto the surface of DCP particles showed significant improvement in the dissolution rate and compression properties of ibuprofen due to an increase in specific surface area when compared with ibuprofen crystallized by other techniques. Additionally, the tablets prepared from ASC powder did not require binder since ibuprofen acted as melt binder during compression.

Conclusion: Directly compressible ibuprofen-loaded DCP particles can serve as an alternative for conventional ibuprofen tablets prepared by wet granulation technique.     

Effect of binder liquid type on spherical crystallization

Aim: Spherical crystallization is a process of formation of agglomerates of crystals held together by binder liquid. This research focused on understanding the effect of type of solvents used as binder liquid on the agglomeration of crystals.

Method: Carbamazepine and ethanol/water were used respectively as a model drug and crystallization system. Eight solvents as binder liquid including chloroform, dichloromethane, isopropyl acetate, ethyl acetate, n-hexane, dimethyl aniline, benzene and toluene were examined to better understand the relationship between the physical properties of the binder liquid and its ability to bring about the formation of the agglomerates. Moreover, the agglomerates obtained from effective solvents as binder liquid were evaluated in term of size, apparent particle density and compressive strength.

Results: In this study the clear trend was observed experimentally in the agglomerate formation as a function of physical properties of the binder liquid such as miscibility with crystallization system. Furthermore, the properties of obtained agglomerates such as size, apparent particle density and compressive strength were directly related to physical properties of effective binder liquids.

Conclusion: Results of this study offer a useful starting point for a conceptual framework to guide the selection of solvent systems for spherical crystallization.     

Ibuprofen ion-exchange fiber complex: improved dissolution and gastric tolerance based on ion exchange

The purpose of the present study is to develop a novel method to improve the dissolution of water-insoluble drug ibuprofen and the gastric tolerance of this non-steroidal anti-inflammatory drug which has potentially serious gastrointestinal side effects. This method is based on ion exchange of ion-exchange fibers. Water-insoluble drug ibuprofen was dispersed in deionized water, and then the ion-exchange fibers in OH^– type was immersed in it. Ibuprofen and the active groups of the ion-exchange fibers combined into ion pairs based on the acid–base reaction. This drug carrier did not release drugs in deionized water, but in water solution containing other ions it would release the drugs into the solution by ion exchange. Confirmed by the X-ray diffraction and the scanning electron microscopy, the ibuprofen combined onto the ion-exchange fibers was in a highly molecular level dispersed state. The improved dissolution of ibuprofen ion-exchange fiber complexes is likely to originate from this ibuprofen’s highly dispersed state. Due to this, ibuprofen’s highly dispersed state, ibuprofen ion-exchange fiber complexes significantly decreases the gastrointestinal side effects of ibuprofen by avoiding the solid ibuprofen’s educing. The present study showed that ibuprofen ion-exchange fiber complexes have the two-fold advantages. One is to improve the dissolution of ibuprofen. The other is to decrease the ibuprofen’s gastrointestinal toxicity.     

Microencapsulation of Ibuprofen by A Coacervation Process Using Eudragit L100-55 as An Enteric Polymer

Ibuprofen microcapsules were prepared using Eudragit as enteric coating material and a simple coacervation method as coating process. Preliminary experiments based on results published with cellulose acetate phthalate led to the formation of a precipitate rather than a coacervate. Adjusting the polarity of the solvent in the Eudragit system by the addition of cosolvents enabled the transformation of the precipitate into a coacervate. This behaviour was qualitatively explained using the solubility parameter approach. The coacervate phase obtained from a system containing 2-propanol as cosolvent was assayed quantitatively in the absence and in the presence of ibuprofen. Due to the increased solubility of the drug in the cosolvent containing system, the composition of the coacervate phase was significantly altered when compared to a system without drug. The surface morphology of the microcapsules was assessed by scanning electron microscopy. The enteric properties of the microcapsules were tested according to the USP XXII test procedures. The permeability of the wall was evaluated by a dissolution test performed at pH 4. During stability testing over a period of 6 months the quality of the ibuprofen microcapsules remained almost unchanged.     

A study of the Mechanisms of Wet Spherical Agglomeration of Pharmaceutical Powders

Spherical agglomeration of a number of chemical and pharmaceutical powders was effected in a stirred liquid mixture using the novel technique developed by Kawashima and Capes, with modifications. The compounds were first classified into four groups on the basis of their solubilities in the liquid systems employed and, accordingly, agglomerated using appropriately developed methods. Each powdered material was first suspended in a liquid medium (external phase) and agglomeration was achieved by addition of a relatively small amount of “bridging” liquid (internal phase) which was immiscible with the (external) dispersion medium. The resulting spherical agglomerates were examined for size, binding strength, and surface topography. It appeared that a considerable number of the suspended particles initially underwent partial dissolution in the bridging liquid. The dissolved portion then collected the undissolved powder into spherical agglomerates under the influence of continuous stirring. Based on the trials and observations on a number of materials ranging from inorganics to organics, the general guidelines for spherical agglomeration of pharmaceutical powders were established. It is hoped that these guidelines will aid the application of this technique in the pharmaceutical and allied industries.     

Modification of Crystal Habit of Ibuprofen Using the Phase Partition Technique: Effect of Aerosil and Tween 80 in Binding Solvent

A ternary diagram, representing the solubility of binding solvent (chloroform) in a mixture of ethanol and water, was constructed. For this study, the solvent mixture that gave the best ibuprofen pellets (IPs) was composed of chloroform:ethanol:water at a ratio of 1.5%:8%:90.5%. The suitable agitator speed, temperature, and mixing time were found to be 1500 rpm, 25°C ± 2°C, and 20 min, respectively. In addition, suitable stirring time when the phase partition process of IPs began was 15 min. IPs obtained from these conditions were small and round, approximately 1 mm; surface determination by scanning electron microscopy (SEM) indicated that the IPs were composed of drug microcrystals rearranged on the surface. For the dissolution, IPs showed lower drug release when compared with pure ibuprofen crystal (IC) (f₂ analysis). An attempt to modify the dissolution property of IP by incorporating various concentrations of Aerosil and Tween 80 in the binding solvent was made. Microscopic appearance showed that both Aerosil and Tween 80 gave less spherical pellets when compared with the use of binding solvent alone. For both the Aerosil and Tween 80 employed, the results indicated a change in rearrangement of drug microcrystals and a change in crystal habit. However, Tween 80 gave more change of the crystallographic direction of drug microcrystals than Aerosil. In term of dissolution, the results showed that employing Tween 80 at 1.2% gave the highest drug release compared to the use of Aerosil and IC alone (f₂ analysis). These pellets had a good flow property, as indicated by Carr's compressibility, flow rate, and angle of repose, and they can be compressed into a tablet, encapsulated by suitable polymer, or pulverized to obtain micronized crystals. In the case of compression into tablets, the dissolution profiles of these tablets compared with those of commercial product meet the USP 24 requirement (Q ≥ 80% at 60 min).     

Modification of Crystal Habit of Ibuprofen Using the Phase Partition Technique: Effect of Aerosil and Tween 80 in Binding Solvent

A ternary diagram, representing the solubility of binding solvent (chloroform) in a mixture of ethanol and water, was constructed. For this study, the solvent mixture that gave the best ibuprofen pellets (IPs) was composed of chloroform:ethanol:water at a ratio of 1.5%:8%:90.5%. The suitable agitator speed, temperature, and mixing time were found to be 1500 rpm, 25°C ± 2°C, and 20 min, respectively. In addition, suitable stirring time when the phase partition process of IPs began was 15 min. IPs obtained from these conditions were small and round, approximately 1 mm; surface determination by scanning electron microscopy (SEM) indicated that the IPs were composed of drug microcrystals rearranged on the surface. For the dissolution, IPs showed lower drug release when compared with pure ibuprofen crystal (IC) (f₂ analysis). An attempt to modify the dissolution property of IP by incorporating various concentrations of Aerosil and Tween 80 in the binding solvent was made. Microscopic appearance showed that both Aerosil and Tween 80 gave less spherical pellets when compared with the use of binding solvent alone. For both the Aerosil and Tween 80 employed, the results indicated a change in rearrangement of drug microcrystals and a change in crystal habit. However, Tween 80 gave more change of the crystallographic direction of drug microcrystals than Aerosil. In term of dissolution, the results showed that employing Tween 80 at 1.2% gave the highest drug release compared to the use of Aerosil and IC alone (f₂ analysis). These pellets had a good flow property, as indicated by Carr's compressibility, flow rate, and angle of repose, and they can be compressed into a tablet, encapsulated by suitable polymer, or pulverized to obtain micronized crystals. In the case of compression into tablets, the dissolution profiles of these tablets compared with those of commercial product meet the USP 24 requirement (Q ≥ 80% at 60 min).     

Microencapsulation of Ibuprofen by A Coacervation Process Using Eudragit L100–55 as An Enteric Polymer

Abstract

Ibuprofen microcapsules were prepared using Eudragit as enteric coating material and a simple coacervation method as coating process. Preliminary experiments based on results published with cellulose acetate phthalate led to the formation of a precipitate rather than a coacervate. Adjusting the polarity of the solvent in the Eudragit system by the addition of cosolvents enabled the transformation of the precipitate into a coacervate. This behaviour was qualitatively explained using the solubility parameter approach. The coacervate phase obtained from a system containing 2-propanol as cosolvent was assayed quantitatively in the absence and in the presence of ibuprofen. Due to the increased solubility of the drug in the cosolvent containing system, the composition of the coacervate phase was significantly altered when compared to a system without drug. The surface morphology of the microcapsules was assessed by scanning electron microscopy. The enteric properties of the microcapsules were tested according to the USP XXII test procedures. The permeability of the wall was evaluated by a dissolution test performed at pH 4. During stability testing over a period of 6 months the quality of the ibuprofen microcapsules remained almost unchanged.     

The control of paracetamol particle size and surface morphology through crystallisation in a spray dryer

The parameters governing the crystallisation of paracetamol using various conventional techniques has been extensively studied, however the factors influencing the drug crystallisation using spray drying is not as well understood. The aim of this work was to investigate the crystallisation of an active pharmaceutical ingredient through evaporative crystallisation using a spray dryer to study the physicochemical properties of the drug and to use semi-empirical equations to gain insight into the morphology and particle size of the dried powder. Paracetamol solutions were spray dried at various inlet temperatures ranging from 60 °C to 120 °C and also from a series of inlet feed solvent compositions ranging from 50/50% v/v ethanol/water to 100% ethanol and solid-state characterisation was done. The size and morphology of the dried materials were altered with a change in spray drying parameters, with an increase in inlet temperature leading to an increase in particle Sauter mean diameter (from 3.0 to 4.4 µm) and a decrease in the particle size with an increase in ethanol concentration in the feed (from 4.6 to 4.4 µm) as a result of changes in particle density and atomised droplet size. The morphology of the dried particles consisted of agglomerates of individual crystallites bound together into larger semi-spherical agglomerates with a higher tendency for particles having crystalline ridges to form at higher ethanol concentrations of the feed.     

Spherical crystallization of celecoxib

Celecoxib exhibits poor flow properties and compressibility. Spherical crystallization of celecoxib was carried out using the solvent change method. An acetone:dichloromethane (DCM):water system was used where DCM acted as a bridging liquid and acetone and water as good and bad solvent, respectively. Hydroxypropylmethylcellulose (HPMC) was used to impart strength and sphericity to the agglomerates. The effect of amount of bridging liquid and speed of agitation was studied using 3² factorial design. Primary properties of the agglomerates were evaluated by infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The effect of variables on micromeritic, mechanical, compressional, and dissolution behavior was evaluated by response surface methodology. Particle size, bulk density, mean yield pressure (MYP), and drug release were found to be significantly affected by either of the two variables. Interaction of variables significantly affected the MYP.     

Spherical Crystallization of Celecoxib

ABSTRACT

Celecoxib exhibits poor flow properties and compressibility. Spherical crystallization of celecoxib was carried out using the solvent change method. An acetone:dichloromethane (DCM):water system was used where DCM acted as a bridging liquid and acetone and water as good and bad solvent, respectively. Hydroxypropylmethylcellulose (HPMC) was used to impart strength and sphericity to the agglomerates. The effect of amount of bridging liquid and speed of agitation was studied using 3² factorial design. Primary properties of the agglomerates were evaluated by infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The effect of variables on micromeritic, mechanical, compressional, and dissolution behavior was evaluated by response surface methodology. Particle size, bulk density, mean yield pressure (MYP), and drug release were found to be significantly affected by either of the two variables. Interaction of variables significantly affected the MYP.     

Crystal Habit Modifications of Ibuprofen and Their Physicomechanical Characteristics

Ibuprofen was crystallized from methanol, ethanol, isopropanol, and hexane at similar conditions. Marked differences in crystal habit of the samples obtained from these solvents were observed. The samples crystallized from methanol and ethanol had a polyhedral crystal habit, while those from hexane were needlelike. Those from isopropanol were elongated crystals. X-ray powder diffraction (XPD) and differential scanning calorimetry (DSC) studies confirmed that these samples were structurally similar; therefore, polymorphic modifications were ruled out. The results showed that crystal habit modification had a great influence on the mechanical properties (compressibility, flow rate, and bulk density) of ibuprofen crystals. Samples obtained from methanol and ethanol exhibited the highest bulk density and the best flow rate, while those from hexane showed the lowest bulk density and the worst flow rate. The samples obtained from ethanol exhibited the best compression force/hardness profiles, and those obtained from hexane produced the softest tablets.