Cocrystalization and simultaneous agglomeration using hot melt extrusion.

PURPOSE: To explore hot melt extrusion (HME) as a scalable, solvent-free, continuous technology to design cocrystals in agglomerated form. METHODS: Cocrystal agglomerates of ibuprofen and nicotinamide in 1:1 ratio were produced using HME at different barrel temperature profiles, screw speeds, and screw configurations. Product was characterized for crystallinity by XRPD and DSC, while the morphology was determined by SEM. Dissolution rate and tabletting properties were compared with ibuprofen. RESULTS: Process parameters significantly affected the extent of cocrystallization which improved with temperature, applied shear and residence time. Processing above eutectic point was required for cocrystallization to occur, and it improved with mixing intensity by changing screw configuration. Product was in the form of spherical agglomerates, which showed directly compressible nature with enhanced dissolution rate compared to ibuprofen. This marks an important advantage over the conventional techniques, as it negates the need for further size modification steps. CONCLUSIONS: A single-step, scalable, solvent-free, continuous cocrystallization and agglomeration technology was developed using HME, offering flexibility for tailoring the cocrystal purity. HME being an established technology readily addresses the regulatory demand of quality by design (QbD) and process analytical technology (PAT), offering high potential for pharmaceuticals.

Effect of oppositely charged polymer and dissolution media on rheology of spray-dried ionic complexes.

The purpose of this research was to address the utility of rheological study in understanding the influence of oppositely charged polymers on release of naproxen sodium encapsulated in chitosan particles. The interaction between oppositely charged kappa-carrageenan (kappa-Ca) and chitosan leads to relatively higher gel strength, which is proportional to the ability to retard the drug release at acidic pH. The oscillatory tests within the linear viscoelastic range where the stress is proportional to the applied strain were performed on the hydrated sample matrices containing chitosan-naproxen sodium spray-dried complexes and k-Ca or hydroxypropyl methylcellulose (HPMC) in various ratios. It was observed that the effect of pH change on the dynamic moduli in spray-dried complexes containing kappa-Ca was much stronger than that with HPMC reflecting presence of strong ionic interaction between kappa-Ca and chitosan. The combination of oppositely charged polymers in different ratios proved to be useful in modulating the rheological properties of the hydrated formulations and their release-retarding properties. Dynamic moduli can be used to measure gel strength and are significant for the interpretation of oral sustained release spray-dried complexes.

Rheological investigation of self-emulsification process.

PURPOSE: Aim of this study is to investigate the mechanism of self-emulsification through rheological analysis of intermediate liquid crystalline (LC) phase formed during self-emulsification process. METHODS: Binary system of tween 80 (T80) and imwitor 742 (I742) was used and different SES were prepared with I742 at 10, 30, 50, 70 and 90% w/w concentration levels. Self-emulsification was monitored by visual observations and droplet size measurement. Mesophases obtained by 50% v/v hydration of SES were utilized for polarizing microscopy, differential scanning calorimetry and rheological studies. RESULTS: Good emulsification with nano sized droplets was observed for SES 30% as compared to micron sized droplets for other SES. In polarizing microscopy, formation of intermediate LC phase was observed in all SES. Lamellar phase was evident in 30% SES while other SES exhibited micellar cubic phase. Presence of high level of structurally bound water in thermal analysis confirmed mesophase formation in all SES. In frequency sweep, decrease in elastic modulus, and an increase in phase degree and loss tangent was observed for 30% SES. Exactly opposite trend was seen in other SES. Thus, rheological studies concluded presence of weak and fragile mesophase structure in 30% SES while LC phase structure with little structural buildup was observed in other SES. This weak mesosphere structure in SES 30% presented no or very little resistance against strain induced deformation. Therefore, during emulsification, weak mesophase in SES 30% ruptured with ease and released jet of nanosize droplets compared to coarse droplets for other SES. CONCLUSION: This study signifies the effect of viscoelastic properties of intermediate LC phase on self-emulsification performance.

Rheological investigation of self-emulsification process: effect of co-surfactant.

PURPOSE: The aim of study is to investigate role of co-surfactant in self-emulsification through rheological analysis of intermediate liquid crystalline (LC) phase formed during self-emulsification. METHODS: To mixture of Captex 200P (C200) and tween 80 (T80) (SES Plain), either medium hydrocarbon chain co-surfactant (Capmul MCM (CMCM): SES C) or long hydrocarbon chain co-surfactant (Peceol (P): SES P) was added separately at different concentration levels. Self-emulsification was monitored by visual observations, turbidimetric and droplet size measurement. Mesophases were obtained by 30% v/v aqueous hydration of SES and characterized by polarizing microscopy, differential scanning calorimetry (DSC) and rheological studies. RESULTS: SES Plain exhibited 'bad' emulsification owing to instantaneous gel formation in aqueous media. Almost all SES C have shown 'good' emulsification with transparent appearance, very low turbidity value and nano size droplets. All SES P presented 'moderate' emulsification with milky appearance, high turbidity value and coarse droplets. Polarizing microscopy revealed formation of lamellar phase in SES Plain and in all SES P while almost all SES C exhibited formation of micellar cubic phase. In DSC studies, higher extent of LC phase formation was observed in SES C as compared to SES P. Rheological study clearly demonstrated presence of elastic and partially recoverable mesophase in SES Plain, which was transformed into a viscous and non-recovering mesophase with addition of CMCM while there was no change in rheological status of SES Plain after addition of P. The weak and viscous LC phase in SES C must have not presented any resistance to strain induced deformation. Therefore, it might have ruptured easily and quickly, releasing jet of nanosize droplets whereas elastic mesophase in SES P might have ruptured with little resistance resulting in coarse droplets. CONCLUSION: The ability of co-surfactant to promote self-emulsification was attributed to their influence on viscoelastic properties of intermediate LC phase.

Cefuroxime axetil solid dispersion with polyglycolized glycerides for improved stability and bioavailability.

OBJECTIVES: Cefuroxime axetil (CA), a poorly soluble, broad spectrum cephalosporin ester prodrug, is hydrolysed by intestinal esterase prior to absorption, leading to poor and variable bioavailability. The objective was therefore to formulate a stable amorphous solid dispersion of the drug with enhanced solubility and stability against enzymatic degradation. METHODS: Spray drying was used to obtain a solid dispersion of CA with Gelucire 50/13 and Aerosil 200 (SDCAGA), and a solid dispersion of CA with polyvinyl pyrrolidone (SDCAP); amorphous CA (ACA) was obtained by spray drying CA alone. The formulations were characterized by differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy studies, and compared for solubility, dissolution and bioavailability in rats. KEY FINDINGS: SDCAP and SDCAGA showed improved solubility and dissolution profiles owing to amorphization and formation of solid dispersions with hydrophilic carriers. The improved stability of amorphous CA in solid dispersions compared to ACA alone was attributed to hydrogen bonding interactions involving the amide of CA with the carbonyl of polyvinyl pyrrolidone in SDCAP, whereas in SDCAGA the interactions were at multiple sites involving the amide and carbonyl of CA with the carbonyl and hydroxyl of Gelucire 50/13. However, SDCAGA showed superior bioavailability compared to SDCAP, ACA and CA. CONCLUSIONS: Improvement in physical stability of solid dispersions was attributed to hydrogen bonding, while improvement in bioavailability of SDCAGA compared to SDCAP, in spite of comparable solubility and dissolution profile, may be attributed to Gelucire, which utilizes intestinal esterase for lipolysis, protecting the prodrug from enzymatic degradation to its non-absorbable base form.

Preparation of multiparticulate vaginal tablet using glyceryl monooleate for sustained progesterone delivery.

Most of the sustained release vaginal formulations are in the form of bioadhesive gels and tablets. Though proved efficient, their presence in the vagina for a longer time as a bulk produces discomfort and interference with body functioning including sexual activities. Hence, they lack complete patient compliance. In this study, multiparticulate vaginal tablets were prepared by utilizing progesterone (PRO) loaded dry powder precursor of cubic phase (DPPCP) of glyceryl monooleate (GMO). DPPCP were obtained by spray drying GMO with magnesium trisilicate (MTS) and have presented PRO sustained release in simulated vaginal fluid (SVF) for 14 hours. The effect of hydrophilic and hydrophobic tableting excipients on compression, phase, bioadhesion and drug release properties of prepared tablets was evaluated. The effervescent hydrophilic tablet (EHT) prepared with hydrophilic excipients showed rapid disintegration but, diminished sustaining ability owing to transformation into lamellar phase whereas the multiparticulate hydrophobic tablet (MHT) obtained from hydrophobic excipients presented both rapid disintegration and sustained release in SVF by virtue of cubic phase retention. During bioadhesivity testing, fast disintegration of MHT with formation of uniform and viscous bioadhesive layer on cow mucosa was observed even with a small volume of SVF. As MHT may not produce discomfort and interference, it will be preferred over bioadhesive gel or tablet.

Preparation of amorphous cefuroxime axetil nanoparticles by sonoprecipitation for enhancement of bioavailability.

The aim of the present work was to prepare amorphous discreet nanoparticles by sonoprecipitation method for enhancing oral bioavailability of cefuroxime axetil (CA), a poorly water-soluble drug. CA nanoparticles (SONO-CA) were prepared by sonoprecipitation and compared with particles obtained by precipitation without sonication (PPT-CA) and amorphous CA obtained by spray drying. Spray drying present broad particle size distribution (PSD) with mean particle size of 10 microm and low percent yield, whereas, precipitation without sonication resulted in large amorphous aggregates with broad PSD. During sonoprecipitation, particle size and yield improve with an increase in the amplitude of sonication and lowering the operation temperature due to instantaneous supersaturation and nucleation. The overall symmetry and purity of CA molecule was maintained as confirmed by FTIR and HPLC, respectively. All the three methods resulted in the formation of amorphous CA with only sonoprecipitation resulting in uniform sized nanoparticles. Sonoprecipitated CA nanoparticles showed enhanced dissolution rate and oral bioavailability in Wistar rat due to an increased solubility attributed to combination of effects like amorphization and nanonization with increased surface area and reduced diffusion pathway.

Effect of drying methods on swelling, erosion and drug release from chitosan-naproxen sodium complexes.

The purpose of this research was to explore theapplication of ionic interactions between naproxen sodium (NS) and chitosan (CH) in complexes (NSC) prepared by tray drying (TD) and spray drying (SD) methods. Drug-polymer ratio (1:1) in the NSC was optimized on the basis of dialysis studies. The particulate systems of NSC were prepared by tray drying (TD) and spray drying (SD) methods. Release retarding polymers were added to the NSC and to the physical mixtures containing NS-CH and their effects on water uptake, matrix erosion and drug release at different pH were compared. Spray dried complexes (SDC) were spherical, free flowing, light and fine amorphous particles in contrast to the crystalline, hard, tenacious, irregularly shaped, denser tray dried complexes (TDC) with poor flowability. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR) patterns confirm the conversion of crystalline to high energy amorphous phase suitable for ionic interactions in NSC. Presence of release retarding polymers, kappa carrageenan and hydroxypropylmethylcellulose (HPMC) in the NSC compacts retarded the drug release and improved the matrix integrity. Carrageenan matrices exhibited more retardation than HPMC tablets. FTIR patterns, erosion, swelling and drug release from matrices support ionic interactions between NS and CH in NSC. The reasons for retarded drug release from the chitosan matrices at acidic pH include poor solubility of drug at acidic pH, formation of a rate limiting polymer gel barrier along the periphery of matrices and the ionic interactions between oppositely charged moieties.

Development of spray-dried co-precipitate of amorphous celecoxib containing storage and compression stabilizers.

The purpose of this study was to obtain an amorphous system with minimum unit operations that will prevent recrystallization of amorphous drugs since preparation, during processing (compression) and further storage. Amorphous celecoxib, solid dispersion (SD) of celecoxib with polyvinyl pyrrollidone (PVP) and co-precipitate with PVP and carrageenan (CAR) in different ratios were prepared by the spray drying technique and compressed into tablets. Saturation solubility and dissolution studies were performed to differentiate performance after processing. Differential scanning calorimetry and X-ray powder difraction revealed the amorphous form of celecoxib, whereas infrared spectroscopy revealed hydrogen bonding between celecoxib and PVP. The dissolution profile of the solid dispersion and co-precipitate improved compared to celecoxib and amorphous celecoxib. Amorphous celecoxib was not stable on storage whereas the solid dispersion and co-precipitate powders were stable for 3 months. Tablets of the solid dispersion of celecoxib with PVP and physical mixture with PVP and carrageenan showed better resistance to recrystallization than amorphous celecoxib during compression but recrystallized on storage. However, tablets of co-precipitate with PVP and carageenan showed no evidence of crystallinity during stability studies with comparable dissolution profiles. This extraordinary stability of spray-dried co-precipitate tablets may be attributed to the cushioning action provided by the viscoelastic polymer CAR and hydrogen bonding interaction between celecoxib and PVP. The present study demonstrates the synergistic effect of combining two types of stabilizers, PVP and CAR, on the stability of amorphous drug during compression and storage as compared to their effect when used alone.

Effect of oppositely charged polymer and dissolution medium on swelling, erosion, and drug release from chitosan matrices.

The reasons for retarded release of naproxen sodium from the chitosan matrices at different pH include poor aqueous solubility of drug, the formation of a rate-limiting polymer gel barrier along the periphery of matrices, the interaction of naproxen sodium with protonated amino groups of chitosan, and the interaction of ionized amino groups of chitosan with ionized sulfate groups of kappa-carrageenan.

Evaluation of a drug with wax-like properties as a melt binder.

The study investigates ibuprofen with wax-like properties as a multifunctional agent (as an active component and as a melt binder). Binding efficiency was compared with granules prepared by wet granulation using polyvinylpyrollidone (PVP K-30) as a binder for micromeritic, physical and mechanical properties such as angle of repose, particle size distribution Carr's index, Hausner's ratio, crushing strength, percentage fines, Heckel plot study and tensile strength. To check the binder distribution during melt granulation, the content uniformity was determined. To check changes in the physical state of ibuprofen, XRPD, DSC and FTIR studies were carried out. The present study underlines the fact that ibuprofen may be adopted as a binder in ibuprofen formulations using the melt granulation technique.

Particle engineering using sonocrystallization: salbutamol sulphate for pulmonary delivery.

The aim of present work was to produce fine elongated crystals of salbutamol sulphate (SS) by sonocrystallization for pulmonary delivery and compare with micronized and spray dried SS (SDSS) for in vitro aerosolization behavior. Application of ultrasound during anti-solvent crystallization resulted in fine elongated crystals (sonocrystallized SS; SCSS) compared to aggregates of large irregular crystals obtained without sonication. Higher sonication amplitude, time, concentration and lower processing temperatures favored formation of smaller crystals with narrow particle size distribution (PSD). SCSS was separated from dispersion by spray drying in the form of loose aggregates (SD-SCSS). The fine particle fraction (FPF) of formulations with coarse lactose carrier in cascade impactor increased from 16.66% for micronized SS to 31.12% for SDSS (obtained by spray drying aqueous SS solution) and 44.21% for SD-SCSS, due to reduced cohesive/adhesive forces and aerodynamic size by virtue of elongated shape of crystals. SD-SCSS was stable without any change in crystallinity and aerodynamic behavior for 3 months at 40 degrees C/75% RH, but amorphous SDSS showed recrystallization with poor aerosolization performance on storage. Sonocrystallization, a rapid and simple technique is reported for production of SS crystals suitable for inhalation delivery.

Ultrasound assisted engineering of lactose crystals.

PURPOSE: To engineer lactose crystals of desired size, shape, surface and particle size distribution (PSD) as a carrier for dry powder inhalers (DPI) by ultrasound assisted in-situ seeding. METHODS: Lactose crystals were obtained from solution by ultrasound assisted in-situ seeding, followed by growth in viscous glycerin solution. The crystals were characterized for physical properties and 63-90 mum size fractions of different batches were mixed with salbutamol sulphate (SS) and compared for in-vitro deposition. RESULTS: Cooling crystallization with stirring for 10-20 h resulted in crystals with wide PSD and varied shape. Application of ultrasound resulted in rapid and complete crystallization in 5 min with rod-shaped fine crystals (15-30 microm) and narrow PSD. In-situ seeded batches yielded micro-fine rod-shaped seed crystals. Seeding followed by growth in glycerin showed desirable size, high elongation ratio, smooth surface and narrow PSD, while growth under stirring showed high elongation ratio with rough surface. Crystals grown in glycerin showed highest dispersibility and fine particle fraction (FPF) of SS. CONCLUSIONS: Ultrasound assisted in-situ seeding, followed by ordered growth in glycerin offers rapid technique for separation of nuclei induction from crystal growth yielding desirable characteristics for better dispersion and in-vitro deposition when employed as DPI carrier.