Physical and chemical characterization of thermosoftened bases for molten filled hard gelatin capsule formulations

Abstract

Dynafill, Dynasan-114, Lutrol-F68, PEG-10000 and PEG-20000 have been examined as potential bases for the preparation of fusion formed solid dispersions for molten filling into hard gelatin capsules. Investigations included, an examination of thermal effects on crystal structure by DSC and XRD, a theological study to evaluate capsule filling characteristics, dissolution studies on drug/base formulations, chemical analysis for free fatty acid impurities in Dynafill and Dynasan-114, and detailed studies on selected drug/base formulations. PEG-20000 and Dynasan-114 were not examined in detail, after preliminary investigations had shown high viscosity and poor filling characteristics for PEG-20000 and poor dissolution characteristics for Dynasan-114. Dynafill provided good release profiles when formulated with a variety of model drugs (Acetohexamide, Ibuprofen, Indomethacin, Quinidine sulphate and Theophylline). Results from hot stage photomicrography supported by DSC and XRD were used to construct a phase diagram of the Ibuprofen/Lutrol-F68 system. The evidence from the phase diagram indicated the formulation of a simple eutectic system with no solid solubility and a eutectic composition at approximately 35% w/w Ibuprofen.     

Rheology and Filling Characteristics of Particulate Dispersions in Polymer Melt Formulations for Liquid Fill Hard Gelatin Capsules

Abstract

The rheology and capsule filling properties of molten excipients, Dynafill, Dynasan-114, Lutrol-F68, and polyethylene glycols (PEG) 6000, 8000, 10,000, and 20,000 have been investigated. Lactose (α-monohydrate) was selected as a model particulate solid with low solubility in PEG in order to investigate the effects of disperse phase particle size, concentration, and PEG molecular weight on rheology and capsule filling properties of these systems. All excipients behaved as Newtonian fluids between 65 and 90°C, which was chosen as a possible temperature range for liquid filling of hard gelatin capsules. The excipients, apart from Dynasan-114 and PEG 20,000, showed satisfactory capsule filling properties at 70°C using a semiautomatic filling machine. Dynasan-114 (viscosity = 0.012 Pass at 70°C) leaked from the seals between the hopper and pump of the filling machine, whereas PEG 20,000 (viscosity = 24 Pas at 70?C) showed bridging of the molten polymer between successive capsule bodies during the filling process. The effect of disperse phase (lactose) particle size and concentration, and continuous phase (PEG) molecular weight on the apparent viscosity and filling properties of the non-Newtonian dispersions were investigated at 70°C. Satisfactory filling of the dispersions was achieved at 70°C up to a limiting concentration of disperse phase which was dependent upon disperse phase particle size and continuous phase molecular weight, and corresponded to a pronounced increase in apparent viscosity of the dispersion.     

Dissolution, Solubility, XRD, and DSC Studies on Flurbiprofen-Nicotinamide Solid Dispersions

Flurbiprofen-nicotinamide solid dispersions were prepared by the fusion method. The solid dispersions were evaluated for dissolution rate. The drug-carrier interaction in the liquid and solid states were studied by using phase solubility analysis, phase diagram, X-ray diffraction (XRD), and differential scanning calorimentry (DSC). Solid dispersions gave fast and rapid dissolution of flurbiprofen compared with the pure drug and the physical mixture. Phase diagram and DSC indicated that flurbiprofen and nicotinamide form a eutectic mixture. The aqueous solubility of flurbiprofen was enhanced in the presence of nicotinamide.     

Dissolution,Solubility, XRD,and DSC Studies on Flurbiprofen-Nicotinamide Solid Dispersions

Flurbiprofen-nicotinamide solid dispersions were prepared by the fusion method. The solid dispersions were evaluated for dissolution rate. The drug-carrier interaction in the liquid and solid states were studied by using phase solubility analysis, phase diagram, X-ray diffraction (XRD), and differential scanning calorimentry (DSC). Solid dispersions gave fast and rapid dissolution of flurbiprofen compared with the pure drug and the physical mixture. Phase diagram and DSC indicated that flurbiprofen and nicotinamide form a eutectic mixture. The aqueous solubility of flurbiprofen was enhanced in the presence of nicotinamide.     

Dissolution, solubility, XRD, and DSC studies on flurbiprofen-nicotinamide solid dispersions

Flurbiprofen-nicotinamide solid dispersions were prepared by the fusion method. The solid dispersions were evaluated for dissolution rate. The drug-carrier interaction in the liquid and solid states were studied by using phase solubility analysis, phase diagram, X-ray diffraction (XRD), and differential scanning calorimentry (DSC). Solid dispersions gave fast and rapid dissolution of flurbiprofen compared with the pure drug and the physical mixture. Phase diagram and DSC indicated that flurbiprofen and nicotinamide form a eutectic mixture. The aqueous solubility of flurbiprofen was enhanced in the presence of nicotinamide.     

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.     

Properties of Solid Dispersions of Naproxen in Various Polyethylene Glycols

Abstract

Solid dispersions of naproxen in polyethylene glycol 4000, 6000, and 20000, aimed at improving the drug dissolution characteristics, were prepared by both the solvent and melting methods. The drug-polymer interaction in the solid state was investigated using differential scanning calorimetry, hot-stage microscopy, Fourier-transform infrared spectroscopy, and x-ray diffraction analysis. Interaction in solution was studied by phase solubility analysis and dissolution experiments. Computer-aided molecular modeling was used to supplement the results from phase solubility studies. No important chemical interaction was found between naproxen and polyethylene glycol, either in solution or in the solid state, apart from the formation of weak drug-polymer hydrogen bonds. The increase of naproxen dissolution rate from its binary systems with polyethylene glycol could be attributed to several factors such as improved wettability, local solubilization, and drug particle size reduction. No influence of polymer molecular weight or of the solid dispersion preparation method on drug dissolution properties was found.     

Investigation of Dissolution Enhancement of Itraconazole by Solid Dispersion in Superdisintegrants

Solid dispersions of itraconazole (ITR) in lactose, microcrystalline cellulose (MCC), and three superdisintegrants (Primogel, Kollidon CL, and Ac-Di-Sol) and their formulation into tablets were investigated with an objective of enhancing the dissolution rate of ITR from tablet formulations. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to characterize the dispersions. A marked enhancement in the dissolution rate of ITR was observed with all the excipients. The order for the excipients to enhance the dissolution rate was Ac-Di-Sol > Kollidon CL > Primogel > MCC > lactose. Solid dispersions in superdisintegrants gave much higher rates of dissolution than the dispersions in other excipients. Ac-Di-Sol gave the most improvement (28-fold) in the dissolution rate of ITR at a 1:1 drug: excipient ratio. Solid dispersions in superdisintegrants could be formulated into tablets. These tablets, apart from fulfilling all official and other specifications, exhibited higher rates of dissolution and dissolution efficiency (DE) values. XRD indicated the presence of ITR in amorphous form in the dispersions. DSC indicated a weak interaction between ITR and the excipients. Micronization and conversion of the drug into the amorphous form and the fast disintegrating and dispersing action of the superdisintegrants contribute to the enhancement of the dissolution rate of ITR from its solid dispersions in superdisintegrants and their corresponding tablet formulations.     

Investigation of dissolution enhancement of itraconazole by solid dispersion in superdisintegrants

Solid dispersions of itraconazole (ITR) in lactose, microcrystalline cellulose (MCC), and three superdisintegrants (Primogel, Kollidon CL, and Ac-Di-Sol) and their formulation into tablets were investigated with an objective of enhancing the dissolution rate of ITR from tablet formulations. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) were used to characterize the dispersions. A marked enhancement in the dissolution rate of ITR was observed with all the excipients. The order for the excipients to enhance the dissolution rate was Ac-Di-Sol > Kollidon CL > Primogel > MCC > lactose. Solid dispersions in superdisintegrants gave much higher rates of dissolution than the dispersions in other excipients. Ac-Di-Sol gave the most improvement (28-fold) in the dissolution rate of ITR at a 1:1 drug:excipient ratio. Solid dispersions in superdisintegrants could be formulated into tablets. These tablets, apart from fulfilling all official and other specifications, exhibited higher rates of dissolution and dissolution efficiency (DE) values. XRD indicated the presence of ITR in amorphous form in the dispersions. DSC indicated a weak interaction between ITR and the excipients. Micronization and conversion of the drug into the amorphous form and the fast disintegrating and dispersing action of the superdisintegrants contribute to the enhancement of the dissolution rate of ITR from its solid dispersions in superdisintegrants and their corresponding tablet formulations.     

Ibuprofen agglomerates preparation by phase separation

The compression ability and dissolution rate of ibuprofen are poor. There are many processes to optimize these properties through adapted formulations. However, it would be more satisfactory to obtain directly during the crystallization step crystalline particles that can be directly compressed and quickly dissolved. This was the aim of this work. Ibuprofen spherical agglomerates were obtained using a very simple method based on the difference of solubility of ibuprofen in ethanol and in water. By cooling down an ibuprofen-saturated solution in an ethanol/water 50/50 mixture from 60°C to room temperature under stirring, a phase separation occurs. Ibuprofen crystallizes in separated water droplets. After separation by sieving and drying, spherical agglomerates were obtained. A study of the physical properties of ibuprofen agglomerates was carried out using electron scanning microscopy and X-ray powder diffraction. The compression ability was tested using an instrumented tablet machine, and the dissolution rate was measured using continuous flow cells. An improvement in compression and dissolution properties of the spherical agglomerates produced was observed. The process of crystallization in a separated dispersed phase could be envisaged each time a drug exhibits opposite solubilities in two miscible solvents.     

Enhanced dissolution and bioavailability of grapefruit flavonoid Naringenin by solid dispersion utilizing fourth generation carrier

Context: Naringenin (NRG), the aglycone flavonoid present in grapefruits, possesses anti-inflammatory, anti-carcinogenic, anti-lipid peroxidation and hepato-protective effects. However, it is poorly soluble in water and exhibits slow dissolution after oral ingestion, thus restricting its therapeutic efficacy.

Objective: With the aim to enhance the dissolution rate and oral bioavailability of NRG, solid dispersion technique has been applied using Soluplus® as carrier.

Methods: Solid dispersions of NRG were prepared by solvent evaporation and kneading methods using various ratios (1:4, 3:7, 2:3 and 1:1) of NRG:Carrier. Characterization of the optimized formulations was performed using Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis. The in vivo behavior of the optimized formulations was also investigated in Wistar Albino rats.

Results: NRG solid dispersion showed a significantly higher solubility and drug dissolution rate than pure NRG (p?Conclusion: Based on these results, it was concluded that solid dispersion technique markedly enhances the in vitro drug release and in vivo behavior of the grapefruit flavonoid NRG.     

Studies on the in vitro Release of Ibuprofen from Polyethylene Glycol-Polyvinyl Acetate Mixtures Liquid Filled into Hard Gelatin Capsules

The release of ibuprofen from mixtures of polyethylene glycol (PEG) with polyvinyl acetate (PVAc) has been studied in vitro and complemented by x-ray diffraction measurements, differential scanning calorimetry (DSC), and melting point determinations via hot-stage microscopy (HSM). Results indicate that ibuprofen release can be affected markedly by alteration of the PVAc concentration. The molecular weight of the PEG and the pH of the dissolution medium are also shown to affect the release profile. Visual observation during the drug release process revealed a complex behavior which included emission of liquidlike droplets, formation of a crust around the releasing mass, and/or production of flakes of solid material. This behavior appeared to have a disadvantageous effect on the reproducibility of drug release. Construction of a phase diagram from results of thermal analysis using DSC and HSM indicated the formation of an eutectic mixture with a composition of 35% ibuprofen and 65% PEG 1500 and a melting point of 36°C. The complex behavior of the drug-releasing mass is discussed in terms of this phase diagram. Only the release data for systems containing 4% w/w or more of PVAc could be linearized by plotting against the square root of time whereas data for all of the systems studied could be linearized by first-order plots.     

Development of Tablets for Controlled Joint Release of Nifedipine and Atenolol

Abstract

Oral combinations of nifedipine and atenolol are widely used in the treatment of hypertension, proving particularly effective when the atenolol is released immediately and the nifedipine is released in a sustained manner. This work examined the potential of combining nifedipine and atenolol in a tablet, which would be easier to manufacture than currently available combined formulations. The results indicated that a 40:60 (w/w) nifedipine-atenolol mixture forms a eutectic melting at 140°C. Nevertheless, both drugs were stable when incorporated in tablets elaborated using cellulose ethers as base excipients. Tablets prepared from atenolol-lactase granules and solid dispersions of nifedipine-hydroxypropylmethylcellulose (100 cP) had more adequate dissolution profiles than a more complex reference formulation in hard capsules.     

Increased dissolution rates of tranilast solid dispersions extruded with inorganic excipients

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as an inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT)-based solid dispersions using continuous melt extrusion (HME) processing. Twin-screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterization showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, in-line NIR studies revealed a possible intermolecular H-bonding formation between the drug and the carrier resulting in the increase of TLT dissolution rates. The capsules containing TLT-extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben^® product.     

Enhancement of solubility and oral bioavailability of manidipine by formation of ternary solid dispersion with d-α-tocopherol polyethylene glycol 1000 succinate and copovidone

Context: Low bioavailability of oral manidipine (MDP) is due to its low water solubility.

Objective: The objective of this study was to increase the solubility and bioavailability of MDP by fabricating ternary solid dispersion (tSD) with d-α-tocopherol polyethyleneglycol-1000-succinate and copovidone.

Methods: In this study, solid ternary phase diagram was applied in order to check the homogeneity of tSD prepared by melting and solidifying with dry ice. The physicochemical properties of different formulations were determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR) and hot stage microscopy. Their solubility, dissolution, stability and bioavailability were also investigated.

Results and discussion: The results demonstrated that tSD obtained from ternary phase diagram divided into homogeneous and non-homogeneous regions. In the homogenous region, the transparent characteristics of tSD was observed and considered as a glass solution, which have a higher MDP solubility than that in non-homogenous region. The hot stage microscopy, DSC and PXRD confirmed that solid dispersion was formed in which MDP was molecularly dispersed in the carriers, especially in the homogenous region of phase diagram. FTIR analysis demonstrated strong hydrogen bonding between amine groups of MDP and carbonyl groups of copovidone, which supported a higher solubility and dissolution of tSD. The pharmacokinetic study in Wistar rats showed that the tSD had the greatest effect on oral bioavailability. Immediate hypotensive effect of tSD was also observed in vivo.

Conclusions: The improvement of stability, dissolution and oral bioavailability of MDP could be achieved by using tSD technique.     

Feasibility of Manufacturing A Solid Dosage Form Using A Liquid Nonvolatile Drug Carrier: A Physico-Chemical Characterization

Experiments were performed to determine the formulation and manufacturing feasibility of three model solid capsule formulations using a spray-on liquid drug carrier. Methylparaben was used as a model low-dose drug in the liquid drug carrier. Formulations containing different amounts of liquid drug carrier were successfully encapsulated on the H&K 400 capsule filling machine. The formulations contained varying ratios of liquid (methylparaben-propylene carbonate solution) to solid (compressible sugar, NF), which ranged from 10.0 - 20.0 μL/450 mg. Physical characteristics (i.e. weight variation, dissolution, etc.) of the filled capsules were evaluated. The 20.0 μL liquid/450 mg solid ratio was found to be the best hard gelatin capsule formulation based upon its rapid dissolution profile and was equivalent to all other formulations tested with respect to weight variation and content uniformity.     

Formulation and delivery strategies of ibuprofen: challenges and opportunities

Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), is mostly administered orally and topically to relieve acute pain and fever. Due to its mode of action this drug may be useful in the treatment regimens of other, more chronic conditions, like cystic fibrosis. This drug is poorly soluble in aqueous media and thus the rate of dissolution from the currently available solid dosage forms is limited. This leads to poor bioavailability at high doses after oral administration, thereby increasing the risk of unwanted adverse effects. The poor solubility is a problem for developing injectable solution dosage forms. Because of its poor skin permeability, it is difficult to obtain an effective therapeutic concentration from topical preparations. This review aims to give a brief insight into the status of ibuprofen dosage forms and their limitations, particle/crystallization technologies for improving formulation strategies as well as suggesting its incorporation into the pulmonary drug delivery systems for achieving better therapeutic action at low dose.     

Nimesulide-modified gum karaya solid mixtures: preparation, characterization, and formulation development

Solid mixtures of nimesulide (NS) and modified gum karaya (MGK) were prepared to improve the dissolution rate of NS. The effect of drug-carrier ratio on dissolution rate of NS was investigated by preparing the solid mixtures of different ratios by cogrinding method. Solid mixtures were also prepared by physical mixing, kneading, and solid dispersion techniques to study the influence of method of preparation. Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), and equilibrium solubility studies were performed to explain the results of in vitro dissolution rate studies. It was clearly evident from the results that the NS dissolution rate was dependent on the concentration of MGK in the solid mixtures, and optimum weight ratio was found to be 1:4 (NS:MGK). Though the dissolution rate of NS from all solid mixtures prepared by different methods improved significantly, maximum improvement in dissolution rate was observed with solid dispersions. The order of methods basing on their effect on dissolution efficiency is solid dispersion > kneading > cogrinding > physical mixing > pure NS. Tablets of pure drug and solid mixtures (1:4 w/w, NS:MGK) were prepared. Though the best results from the dissolution test were obtained for the tablets containing solid dispersions, tablets containing cogrinding mixture were found to be suitable, from a practical point of view, for commercialization.     

Influence of eutectic mixture as a multi-component system in the improvement of physicomechanical and pharmacokinetic properties of diacerein

A multi-component system of diacerein (DIA) with 2, 4 – dihydroxybenzoic acid (DHA) as coformer at various molar compositions was formulated to simultaneously improve solubility, compressibility and bioavailability of DIA by applying acetone assistant grinding technique. Various evaluation parameters pertaining to measure physicomechanical properties were conducted. Thermal analysis revealed a ‘V’-shaped binary phase diagram along with single melting event as a possibility of eutectic formation between drug and coformer. It was further confirmed PXRD and FT-IR. Equidimensional shape with platy nature of eutectic material was observed in SEM images imparting its better flow and compressibility. Solubility and dissolution study showed 2 and 1.8 folds enhancement respectively compared to pure DIA and control batch. Pharmacokinetic study proved 2.1 times higher bioavailability in case of prepared eutectic compared to DIA along with its stable nature. Hence, the multi-component system can become a potential way for the improvement of material characteristics.     

Preparation,Characterization and In Vitro Evaluation of Solid Dispersions Containing Docetaxel

Solid dispersions using water-soluble carriers were studied for improving the dissolution of docetaxel, a poorly soluble compound. In order to obtain the most optimized formulation, we prepared many solid dispersions with different carriers, different solvents, or at a series of drug-to-carrier ratios, and compared their dissolution. The accumulative dissolution of docetaxel from poloxamer 188 was more excellent than that from PVP_k30 and glyceryl monostearate, and the dissolution of docetaxel from solid dispersion was markedly higher than that of pure docetaxel; meanwhile the increased dissolution was partly dependent on the ratios of docetaxel and poloxamer 188. The ethanol used to prepare solid dispersion is of more significant effect on the dissolution of docetaxel than that of acetone. The docetaxel/poloxamer 188 system was characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), and environmental scanning electron microscope (ESEM). The results of DSC, XRD, and ESEM analyses of docetaxel/poloxamer 188 system showed that there are intermolecular interactions between docetaxel and poloxamer, and the crystallinity of docetaxel disappeared. These results show that solid dispersion is a promising approach of developing docetaxel drug formulates.