Hot-melt Method Research Articles

Thermal and spectroscopic analysis of inclusion complex of spironolactone prepared by evaporation and hot melt methods

Solvent and melt techniques were used to obtain molecular dispersion of the poorly soluble spironolactone (SPIR) model drug enhancing its dissolution rate. DSC study of the interaction between SPIR and hydroxypropyl-β-cyclodextrin confirmed the need for molecular dispersion if their complexation is required. Solvent-free twin-screw extrusion was suitable for forming inclusion complex significantly below the melting temperature of the SPIR. According to DSC, Raman and XRPD results fine dispersion of both components was achieved in a hydrophilic polymer. The molecules of the active ingredient are separated from each other in the polymer and the lack of the lattice energy causes faster dissolution.

Characterisation of the thermal, spectroscopic and drug dissolution properties of mefenamic acid and polyoxyethylene–polyoxypropylene solid dispersions

The aim of this study was to investigate the solubility of mefenamic acid (MA), a highly cohesive, poorly water-soluble drug in a copolymer of polyoxyethylene–polyoxypropylene (Lutrol F68®), and to understand the effect drug polymer solubility has on in vitro dissolution of MA. Solid dispersions (SD) of MA were prepared by a hot melt method, using Lutrol F68® as a thermoplastic polymeric platform. High-speed differential scanning calorimetry (Hyper-DSC), Raman spectroscopy, powder X-ray diffractometry (PXRD) and hot-stage/fluorescence microscopy were used to assess the solubility of the drug in molten and solid polymer. Drug dissolution studies were subsequently conducted on single-phase solid solutions and biphasic SD using phosphate buffer pH 6.8 as dissolution media. Solubility investigations using Hyper-DSC, Raman spectroscopy and hot-stage microscopy suggested MA was soluble in molten Lutrol F68® up to a concentration of 35% (w/w). Conversely, the solubility in the solid-state matrix was limited to <15% (w/w); determined by Raman spectroscopy, PXRD and fluorescence microscopy. As expected the dissolution properties of MA were significantly influenced by the solubility of the drug in the polymer matrix. At a concentration of 10% (w/w) MA (a single phase solid solution) dissolution of MA in phosphate buffer 6.8 was rapid, whereas at a concentration of 50% (w/w) MA (biphasic SD) dissolution was significantly slower. This study has clearly demonstrated the complexity of drug–polymer binary blends and in particular defining the solubility of a drug within a polymeric platform. Moreover, this investigation has demonstrated the significant effect drug solubility within a polymeric matrix has upon the in vitro dissolution properties of solid polymer/drug binary blends. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4545–4556, 2009

Improvement of solubility and dissolution rate of indomethacin by solid dispersions in Gelucire 50/13 and PEG4000

The aim of this study was to prepare and characterize solid dispersions of water insoluble non-steroidal anti-inflammatory drug, indomethacin (IND), with polyethylene glycol 4000 (PEG4000) and Gelucire 50/13 (Gelu.) for enhancing the dissolution rate of the drug. The solid dispersions (SDs) were prepared by hot melting method at 1:1, 1:2 and 1:4 drug to polymer ratios. Scanning electron microscopy (SEM), X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to examine the physical state of the drug. Furthermore, the solubility and the dissolution rate of the drug in its different systems were explored. The data from the XRD showed that the drug was still detectable in its solid state in all SDs of IND–Gelu. and disappeared in case of higher ratio of IND–PEG4000. DSC thermograms showed the significant change in melting peak of the IND when prepared as SDs suggesting the change in crystallinity of IND. The highest ratio of the polymer (1:4) enhanced the drug solubility about 4-folds or 3.5-folds in case of SDs of IND–PEG or IND–Gelu., respectively. An increased dissolution rate of IND at pH 1.2 and 7.4 was observed when the drug was dispersed in these carriers in form of physical mixtures (PMs) or SDs. IND released faster from the SDs than from the pure crystalline drug or the PMs. The dissolution rate of IND from its PMs or SDs increased with an increasing amount of polymer.

Preformulation Studies of a Prodrug of Δ9-Tetrahydrocannabinol

Preformulation studies were performed on a hemiglutarate ester prodrug of Delta(9)-tetrahydrocannabinol (THC-HG), to facilitate the development of stable formulations by hot-melt methods. The various studies performed included solid-state thermal characterization, pKa, logP, aqueous and pH dependent solubility, pH stability and effect of moisture, temperature and oxygen on solid-state stability. A hot-melt method was utilized to fabricate THC-HG incorporated poly (ethylene oxide) (PEO) matrices and the bioadhesive properties, release profiles and post-processing stability of these matrices were assessed as a function of the polymer molecular weight. The prodrug exhibited a T (g) close to 0 degrees C, indicating its amorphous nature. Thermogravimetric analysis revealed a rapid weight loss after 170 degrees C. The prodrug exhibited a seven-fold higher aqueous solubility as compared to the parent drug (THC). Also, the solubility of the compound increased with increasing pH, being maximum at pH 8. The prodrug exhibited a v-shaped pH-rate profile, with the degradation rate minimum between pH 3 and 4. The moisture uptake and drug degradation increased with an increase in relative humidity. Solid-state stability indicated that the prodrug was stable at -18 degrees C but demonstrated higher degradation at 4 degrees C, 25 degrees C and 40 degrees C (51.6%, 74.5% and 90.1%, respectively) at the end of 3-months. THC-HG was found to be sensitive to the presence of oxygen. The release of the active from the polymeric matrices decreased, while bioadhesion increased, with an increase in molecular weight of PEO.

Development and Characterization of Zaleplon Solid Dispersion Systems: A Technical Note

Zaleplon (Fig. 1) is a pyrrazolopyrimidine hypnotic drug indicated for the short term (2 to 4 weeks) management of insomnia (1). It interacts with GABAA receptor and also shows some pharmacological properties of benzodiazepines (2). It also possesses potent anticonvulsant activity against pentylenetetrazole- and electroshock-induced convulsions (3) and is rapidly and completely absorbed after oral administration. However, it undergoes extensive first pass hepatic metabolism after absorption, with only 30% of zaleplon being systemically available (4). Zaleplon attains peak concentration (Cmax) within 1.1 h (tmax) approximately after administration, with terminal elimination half life of 1 hour (5). Cmax and area under the plasma concentration–time curve (AUC) both exhibit linear dose proportionality at doses up to 60 mg well above the 10 mg therapeutic dose (6,7). Fig. 1 Chemical structure of zaleplon Although zaleplon is rapidly absorbed after oral administration, its poor aqueous solubility (8) (practically insoluble) can make its absorption dissolution rate limited and thus delay onset of action. The dissolution of drugs is a prime determinant in the absorption of poorly water-soluble drugs and also serves as a rate-limiting step (9). No information is available on the improvement of these drug-like properties of zaleplon. In this article increasing the solubility of zaleplon has been addressed via solid dispersion technique. The formulation of poorly water-soluble drugs is one of the most challenging tasks to the formulation experts. An enhancement in the solubility and the dissolution rate can improve the oral bioavailability of such drugs, which further improves the therapeutic efficacy and patient compliance. Various techniques have been used to enhance the solubility of poorly water-soluble drugs, including the use of surfactants (10), inclusion complexation (11), use of polymorph (12), and amorphous form of drug micronisation (13) and solid dispersion (14–16). The solubilization of drug from solid dispersion systems is mainly because of the reduction in particle size, increase in the surface area and reduction in the crystallinity that improves dissolution rate. Also, no energy is required to break up the crystal lattice of a drug during dissolution process and drug solubility and wettability may be increased by surrounding hydrophilic carriers (17). The various methods used to prepare solid dispersions are the hot melt method (18,19), solvent evaporation (20), spray drying (21), hot melt extrusion (22), solvent deposition technique (23) and solvent wetting method (24). The aim of the present study was to enhance the dissolution rate of zaleplon using solid dispersion technique with various hydrophilic polymers. The solvent evaporation method was used to prepare solid dispersion particles of zaleplon. Solid dispersion systems and physical mixtures of zaleplon were prepared with poloxamer F68, polyvinylpyrrolidone K30 (PVP K30), and polyethyleneglycol 6000 (PEG 6000) each in 1:1, 1:3 and 1:5 ratios. The selection of different ratios of polymers was purely on random basis. The solid-state properties of these binary systems were studied by thin layer chromatography, Fourier transformation infrared spectroscopy, X-ray powder diffractometry and differential scanning calorimetry. The dissolution behavior of zaleplon and its binary systems were further evaluated.

Characterization of the distribution, polymorphism, and stability of nimodipine in its solid dispersions in polyethylene glycol by micro-Raman spectroscopy and powder x-ray diffraction

In the present study, a series of solid dispersions of the drug nimodipine using polyethylene glycol as carrier were prepared following the hot-melt method. Micro-Raman spectroscopy in conjunction with X-ray powder diffractometry was used for the characterization of the solid structure, including spatial distribution, physical state, and presence of polymorphs, as well as storage stability of nimodipine in its solid formulations. The effect of storage time on drug stability was investigated by examination of the samples 6 months and 18 months after preparation. Confocal micro-Raman mapping performed on the samples showed that the drug was not uniformly distributed on a microscopic level. The presence of crystals of nimodipine with sizes varying between one and several micrometers was detected, and the crystal size seemed to increase with overall drug content. In samples examined 6 months after preparation it was found that the crystals existed mainly as the racemic compound, whereas after 18 months of storage mainly crystal conglomerates were observed.

Polymeric Systems for Amorphous Δ9-Tetrahydrocannabinol Produced by a Hot-melt Method. Part II: Effect of Oxidation Mechanisms and Chemical Interactions on Stability

The objectives of the present research investigations were to (i) elucidate the mechanism for the oxidative degradation of Δ9-tetrahydrocannabinol (THC) in polymer matrix systems prepared by a hot-melt fabrication procedure, and (ii) study the potential for controlling these mechanisms to reduce the degradation of THC in solid dosage formulations. Various factors considered and applied included drug-excipient compatibility, use of antioxidants, cross-linking in polymeric matrices, microenvironment pH, and moisture effect. Instability of THC in polyethylene oxide (PEO)-vitamin E succinate (VES) patches was determined to be due to chemical interaction between the drug and the vitamin as well as with the atmospheric oxygen. Of the different classes and mechanisms of antioxidants studied, quenching of oxygen by reducing agents, namely, ascorbic acid was the most effective in stabilizing THC in PEO-VES matrices. Only 5.8% of the drug degraded in the ascorbic acid-containing patch as compared to the control (31.6%) after 2 months of storage at 40°C. This coupled with the cross-linking extent and adjustment of the pH microenvironment, which seemed to have an impact on the THC degradation, might be effectively utilized towards stabilization of the drug in these polymeric matrices and other pharmaceutical dosage forms. These studies are relevant to the development of a stable transmucosal matrix system for the therapeutic delivery of amorphous THC.

Effect of physical state and particle size distribution on dissolution enhancement of nimodipine/PEG solid dispersions prepared by melt mixing and solvent evaporation.

The physical structure and polymorphism of nimodipine were studied by means of micro-Raman, WAXD, DSC, and SEM for cases of the pure drug and its solid dispersions in PEG 4000, prepared by both the hot-melt and solvent evaporation methods. The dissolution rates of nimodipine/PEG 4000 solid dispersions were also measured and discussed in terms of their physicochemical characteristics. Micro-Raman and WAXD revealed a significant amorphous portion of the drug in the samples prepared by the hot-melt method, and that saturation resulted in local crystallization of nimodipine forming, almost exclusively, modification I crystals (racemic compound). On the other hand, mainly modification II crystals (conglomerate) were observed in the solid dispersions prepared by the solvent evaporation method. However, in general, both drug forms may appear in the solid dispersions. SEM and HSM microscopy studies indicated that the drug particle size increased with drug content. The dissolution rates were substantially improved for nimodipine from its solid dispersions compared with the pure drug or physical mixtures. Among solid dispersions, those resulting from solvent coevaporation exhibited a little faster drug release at drug concentrations lower than 20 wt%. Drug amorphization is the main reason for this behavior. At higher drug content the dissolution rates became lower compared with the samples from melt, due to the drug crystallization in modification II, which results in higher crystallinity and increased particle size. Overall, the best results were found for low drug content, for which lower drug crystallinity and smaller particle size were observed.

Chemical stabilization of a Δ9-tetrahydrocannabinol prodrug in polymeric matrix systems produced by a hot-melt method: Role of microenvironment pH.

This research was conducted in order to fabricate stable polyethylene oxide (PEO)-based transmucosal systems of a Δ9-tetrahydrocannabinol (THC) prodrug, a hemisuccinate ester, using a hot-melt method. Since Δ9-tetrahydrocannabinol (THC-HS) was heat labile, a series of processing aids were evaluated in order to facilitate hot-melt production at lower temperatures, thereby reducing THC-HS degradation. The stability of THC-HS was influenced both by the processing conditions such as heating time and temperature, and the postprocessing storage conditions. The type of formulation additive also affected the extent of degradation. In the presence of polyethylene glycol (PEG)-400, the percentage of relative degradation of THC-HS to THC was 13.5% and 49.4% at 80°C and 120°C, respectively. In contrast, incorporation of vitamin E succinate (VES) reduced processing degradation to 2.1% and 9.2%, respectively, under the same conditions. Severe degradation of THC-HS was observed during storage, even under freezing conditions (-18°C). A VES-Noveon AA-1 combination was observed to best stabilize the prodrug systems both during processing and postprocessing. Stabilization of THC-HS was achieved in these polyethylene oxide matrices at 4°C, with almost 90% of theoretical drug remaining for up to 8 months. Investigation of the pH effect revealed that the pH of the microenvironment in these polymeric systems could be modulated to significantly improve the stability of THC-HS, degradation being the least in a relatively acidic medium.

Synthesis of a novel siloxane-containing diamine for increasing flexibility of epoxy resins

A new siloxane-containing curing agent (ETSO–DDM) was synthesized from epoxy-terminated siloxane oligomer (ETSO) and 4,4′-diaminodiphenyl methane (DDM) with a hot-melt method. And its structure was characterized by means of FT-IR, 1H NMR, and 13C NMR spectra. The thermal stabilities and the mechanical behaviors of diglycidylether of bisphenol A (DGEBA) epoxy resins cured with ETSO–DDM were examined. The thermal stability factors, such as the initial decomposition temperature (IDT), temperature of maximum rate of degradation ( T max), and decomposition activation energy ( E t), of the DGEBA/ETSO–DDM systems were increased with increasing the ETSO content up to 5 wt% ETSO. The mechanical properties were increased and the internal stress of the cured epoxy resins was decreased as the ETSO content increased. This could be interpreted in terms of the introduction of soft siloxane segment into the epoxy network, which can be attributed to the increasing of the flexibility or decreasing of the internal stress in the DGEBA/ETSO–DDM systems.

Physical properties and dissolution behaviour of nifedipine/mannitol solid dispersions prepared by hot melt method

Solid dispersions of nifedipine (NIF) with mannitol in preparations containing 10 and 50% (w/w) of drug were manufactured by the hot melt method. Physical properties and the dissolution behaviour of binary systems as physical mixtures and solid dispersions were investigated. In all samples, the crystal structure of NIF was confirmed using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). Fourier transform infrared spectroscopy (FTIR) revealed, there was no interaction between drug and carrier, however, FTIR spectra indicated formation of thermodynamically less stable polymorph of mannitol. The dissolution rate of NIF from solid dispersions was markedly enhanced, the effect being stronger at higher drug loading (50%, w/w, NIF). The dissolution rate enhancement was attributed to improved wetting of NIF crystals due to mannitol particles, attached on the surface, as inspected by means of SEM. Thermal stability of NIF, mannitol and two other potential carbohydrate carriers (lactose and saccharose) during the hot melt procedure was investigated using 1H NMR. NIF was found to be thermically stable under conditions applied. As expected, among carriers only mannitol demonstrated suitable resistance to high temperature used in experiments.

Comparison of chitosan and gelatin coated microparticles: prepared by hot-melt method

The aim of this study was to compare the performance of microparticles and their release properties after coating by chitosan and gelatin, respectively. All of the poly(ϵ-caprolactone) (PCL) microparticles were prepared by the hot-melt encapsulation method and indomethacin was selected as a model drug to be encapsulated. All of the coated microparticles retained their spherical shape irrespective of the type of coating material, and the particle size of coated microparticles was similar to the uncoated ones. The indomethacin encapsulation efficiency was in the range of 8.65±0.08%–8.81±0.04% for uncoated microparticles and 8.22±0.04%–8.68±0.08% for coated microparticles. The release of indomethacin from uncoated microparticles followed a two-exponential release profile, where indomethacin was rapidly released within 4 h during the first release phase, after that ∼20% of the drug was continuously and slowly released for up to 24 h in the second phase. The similar release profile was observed from coated microparticles irrespective of the times of coating and the types of coating material. Both the natural coating materials, chitosan and gelatin, efficiently reduced the initial burst release and the first phase of drug release, but did not alter the second phase of drug release. In other words, chitosan and gelatin could be used to protect the drug on the surface of microparticles from immediately contacting with the release medium and both possessed the same feature in the delay of drug release.

Comparison of chitosan and gelatin coated microparticles: Prepared by hot-melt method

The aim of this study was to compare the performance of microparticles and their release properties after coating by chitosan and gelatin, respectively. All of the poly(ϵ-caprolactone) (PCL) microparticles were prepared by the hot-melt encapsulation method and indomethacin was selected as a model drug to be encapsulated. All of the coated microparticles retained their spherical shape irrespective of the type of coating material, and the particle size of coated microparticles was similar to the uncoated ones. The indomethacin encapsulation efficiency was in the range of 8.65±0.08%–8.81±0.04% for uncoated microparticles and 8.22±0.04%–8.68±0.08% for coated microparticles. The release of indomethacin from uncoated microparticles followed a two-exponential release profile, where indomethacin was rapidly released within 4 h during the first release phase, after that ∼20% of the drug was continuously and slowly released for up to 24 h in the second phase. The similar release profile was observed from coated microparticles irrespective of the times of coating and the types of coating material. Both the natural coating materials, chitosan and gelatin, efficiently reduced the initial burst release and the first phase of drug release, but did not alter the second phase of drug release. In other words, chitosan and gelatin could be used to protect the drug on the surface of microparticles from immediately contacting with the release medium and both possessed the same feature in the delay of drug release.

The Release of 5-Fluorouracil from Microspheres of Poly(ε-Caprolactone-co-ethylene Oxide)

The purpose of this study was to evaluate the in vitro release of 5-fluorouracil from microspheres prepared using a novel triblock copolymer of ε-caprolactone and ethylene oxide as the encapsulating material. Microspheres of poly(ε-caprolactone-co-ethylene oxide) were prepared by employing the “hot-melt” method of microencapsulation. Microspheres were sized using sieve analysis and scanning electron microscopy (SEM). Release studies were performed using a custom-made rotating paddle dissolution apparatus. Copolymer microspheres, fabricated by the hot melt method were shown by electron microscopy to have smooth, nonporous surfaces. Drug-loaded microspheres were found to have a broad distribution of sizes, which was thought to be a consequence of the wide range of crystal sizes of the encapsulated unmilled drug. Nonlinear release kinetics were observed from microspheres in the size fraction 75–250 μm, with a pronounced “burst release” associated with the presence of drug at the surface of the microspheres. A specific delineation of the drug release mechanism was not possible due to rapid gelation, swelling, and subsequent dissolution of the microspheres that occurred on hydration. This work describes the preparation of microspheres that swell rapidly and coalesce together on hydration, accompanied by rapid drug release and copolymer dissolution over a 2-hr period.

The mechanism and model reactions of epoxy-polycarbonate blends cured with aliphatic amine

The reaction mechanism of a polycarbonate (PC) and epoxy blend cured with aliphatic amine was investigated. The spectroscopic variations of the PC-epoxy blend cured by aliphatic amines indicate that the carbamates and ureas appeared in the system. Various methods to prepare the blends were used: (1) PC dissolved in epoxy by hot melt method to obtain the PC-epoxy blend and the aliphatic amine then added to cure the blend. (2) PC dissolved in aliphatic amine by solvent to obtain the PC-aliphatic amine mixture and the epoxy added to cure the mixture. Method (1) yields carbamates at the beginning, and the compound is decomposed at 80°C to release isocynates that will react with the hydroxyl group of network to form another carbamate structure. The carbamates formed crosslinked with epoxy at the final stage. Method (2) gives ureas at the initial stage and most of the ureas undergo a substitute reaction with the hydroxyl group of the cured resin to yield the carbamate structure crosslinking with the cured epoxy network. The differences of the resultant products between the two preparing procedures are investigated by calculating the content of crosslinker, plasticizer and chain end.

Synthesis and impact properties of siloxane-DGEBA epoxy copolymers

Siloxane-incorporated epoxy (ESDG) copolymers were prepared by a hot-melt method. IR, 1H- and 13C-NMR are used to determine the structures. The data on the molecular properties indicate that reaction proceeded with a random polycondensation without involving the opening of the oxirane ring in the epoxy structure. Lowering Tgs with increasing siloxane content in copolymers are observed except for the copolymer modified with PDMS siloxane oligomer. Thermal stability data indicate that siloxane moiety exerts its thermal stability on the copolymer through dissipation of the heat, thus delaying thermal degradation of copolymers. Increasing impact strengths in J/M in the range of 22.0–59.0 are observed for copolymers and the improvement of the impact strength is closely related to the structure and content of siloxane oligomers in copolymers. A rough surface was observed by SEM examination on the propagation surface of the copolymeric impact specimen, while a smooth surface is observed on the unmodified epoxy specimen. The EDX analysis reveals these protruded features are Si-rich segments. The morphological observations suggest the siloxane segment may act as a toughening agent in the epoxy networks, thus contributing to the impact improvement of the copolymers. © 1996 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 34:1907–1922, 1996

4477636 Hot-melt adhesive and method

4477636 Hot-melt adhesive and method