RESUMO
BACKGROUND: Direct compression is potentially sensitive to particle size distribution (PSD) variability in pharmaceutical grade excipients. Yet, the impact is insufficiently studied. Furthermore, the use of force sensor as a process analytical technology (PAT) platform, to monitor the effect of PSD variations on compact tensile strength, is a readily available but underutilized strategy. METHODS: To address these shortfalls, the effect of PSD variability on compaction was investigated. Low (4% w/w drug) and high (15% w/w drug) dose blends comprising chlorpheniramine, microcrystalline cellulose and spray-agglomerated lactose were tableted. The PSD of spray-agglomerated lactose was varied by adding ungranulated fines to simulate commercially-relevant variability. Tensile strength and disintegration time were determined. The use of force sensor, to generate force-displacement and force-time profiles, for in-line tensile strength prediction was evaluated. RESULTS: Increasing proportion of ungranulated fines (≥ 16%) reduced tensile strength by 10% and 4% in low and high dose formulations (p < 0.02). Increased friction during compaction hindered particle movement and reduced the energy available for bonding. Nevertheless, disintegration performances were equally acceptable for immediate drug release (≈ 30 s). Modelling of tensile strength with force-displacement and force-time profiles yielded ≥ 98% accuracy for in-line prediction (relative root mean square error of prediction = 3.7% and 4.8%). CONCLUSION: A better understanding of the relationship between PSD variability and direct compression was attained; and force-displacement and force-time profiling are pragmatic and elegant PAT strategies. Significantly, with further refinements, the force sensor in the rotary tablet press can be repurposed for process monitoring and quality inspection. This unlocks opportunities for process understanding and control, without additional investments in PAT platforms.
Assuntos
Excipientes , Tecnologia Farmacêutica , Composição de Medicamentos , Tamanho da Partícula , Comprimidos , Resistência à TraçãoRESUMO
BACKGROUND: Particle size distribution (PSD) variability in excipients affects mixing. In response, manufacturers rely on raw material control and rigidly defined process parameters to achieve quality. However, this status quo is costly; and diverges from regulatory exceptions for process robustness. Although robustness improves cost and material usage efficiency, it remains under-adopted. METHOD: To address this gap, a robust batch mixing operation that mitigated the impact of PSD variability was evaluated, with blends comprising chlorpheniramine, microcrystalline cellulose and lactose. PSD of lactose was varied to simulate commercially-relevant variability. Due to PSD-induced rheological variations, the blends had different optimal mixing speeds. For the automation study, near infrared (NIR) spectroscopy; process optimization and endpoint detection algorithms; and control hardware were integrated within a cluster of software environments. NIR spectroscopy was employed for in-line PSD characterization and blend monitoring, to modulate mixing speed and detect endpoint (feedforward and feedback control). RESULTS: NIR spectroscopy rapidly detected PSD variations by the 6th-9th rotations, to activate feedforward control, which mitigated the effect of PSD variability and reduced the mixing time by 13-34%. Endpoints were correctly detected. PSD variations and blend homogeneity were accurately predicted (relative standard error of prediction ≤ 2%). CONCLUSION: The automated robust mixing operation was successful. Pertinently, NIR spectrometer can be adopted for multimodal sensing. Its applicability for production-driven characterization of raw materials in batch and continuous pharmaceutical processing should be further explored. Lastly, this study laid the groundwork for end-to-end implementation of process analytical technology in robust batch processing.
Assuntos
Celulose/química , Clorfeniramina/química , Excipientes/química , Lactose/química , Tecnologia Farmacêutica , Automação , Composição de Medicamentos , Tamanho da Partícula , Pós , Controle de Qualidade , Espectroscopia de Luz Próxima ao Infravermelho , Fatores de TempoRESUMO
BACKGROUND: This study reports the use of multivariate time and image analysis of avalanche videographic data for quantitative visual modelling of mixability. Its usefulness, in mechanistically modelling a powder's rheological behavior in relation to mixing, was evaluated. METHODS: Particle size distribution (PSD) of a pharmaceutical grade lactose powder was modified to reflect commercially encountered variability. The PSD variants were rheologically distinct and had different mixability. Avalanche testing was performed on the modified lactose powders. Avalanche rheological properties (ARP) profiles and videos were collected for numerical and quantitative visual modelling, respectively. In quantitative visual modelling, videos captured were transformed into serial projected images. Important features of the projected images were extracted as eigen-images, to derive the avalanche rheological visual metric (ARVM). Mixability was modelled as a function of ARP or ARVM and the rotation speed. RESULTS: Relative to the ARP model, the ARVM models were highly interpretable. As a univariate expression of ARP, ARVM also possessed construct validity (r2 greater than 0.99, slope ≥ 0.96). Important rheological features of the lactose powders were holistically visualized within a single eigen-image which enabled the generation of simpler models (5 versus 34 variables for ARP model). The ARVM models predicted mixability of lactose powders with greater accuracy than the ARP model (relative root mean square error of external validation ≤ 3.30% versus 4.96%). CONCLUSIONS: Quantitative visual modelling is a viable alternative to purely numerical approaches. Most significantly, the model's interpretability and concreteness enable manufacturers to readily understand the risk posed by PSD variability on manufacturing processes and swiftly take pre-emptive actions, without being mired in multivariate data complexity. In addition, the use of quantitative visual approach in time series imaging, for studying and monitoring industrial processes, could also be explored.
Assuntos
Composição de Medicamentos/métodos , Imageamento Tridimensional/métodos , Lactose/química , Pós/química , Excipientes/química , Análise Multivariada , Tamanho da Partícula , Reologia/métodosRESUMO
The utility of modulating rotation speed in tumble mixing and its mechanistic interplay with particle size distribution (PSD) variability in excipients remain underexplored. They were investigated in this study. For the present purpose, PSD of a commercial grade lactose was modified to reflect commercially relevant variations; and mixed with microcrystalline cellulose and chlorpheniramine in a double-cone blender, at various rotation speeds. Model of mixing was constructed using avalanche rheological properties and was also rendered as quantifiable visual models using avalanche rheological visual metric (ARVM), to uncover mechanistic relationships. ARVM was derived through multivariate image analysis of avalanche flow. It was observed that increasing rotation speed reduced the number of rotations needed to achieve blend homogeneity by 30-33% for PSD variants with 16-20% fines, while increasing the number of rotations by 134% in PSD variants with less than 15% fines (p ≈ 0.00). ARVM successfully modelled (root mean square error of external validation = 2.46%) and revealed the mechanistic interplay. With increased proportion of fines, lactose exhibited quasi-parabolic motion with disaggregation of soft agglomerates and improved mixing. With decreased proportion of fines, lactose flowed as coherent wave-like masses with imperceptible dispersive tendency and increased dilation, which impeded mixing. In conclusion, this study contributes to process understanding and ideas for designing robust mixing operations. It showcases the usefulness of a quantitative visual approach, exemplified by the ARVM, to evaluate material variability and uncover its mechanistic impact on processing.
Assuntos
Composição de Medicamentos/métodos , Excipientes/química , Química Farmacêutica , Tamanho da Partícula , ReologiaRESUMO
Particle size distribution (PSD) variability in excipients may cause unacceptable prolongation of mixing time needed to achieve blend homogeneity. Therefore, it is vital to modulate mixing through real-time monitoring of PSD variability. Notwithstanding the criticality of PSD variability, real-time measurement of PSD during mixing is relatively unexplored; and this is the focus of the present study. The model excipient was commercial grade lactose with modified PSD that conformed to the manufacturer's specifications. It was mixed with microcrystalline cellulose and chlorpheniramine in a double-cone blender. High and low dose blends were prepared and near infrared spectroscopy (NIRS) was used to collect spectral data, during mixing, for chemometric modelling of PSD. Four modelling approaches based on partial least squares regression (PLSR) were applied. The models were highly interpretable and rapidly measured PSD near the beginning of mixing (5th to 6th rotation), with accuracy (relative standard error of prediction <5.0%, r2â¯≈â¯1.00, slopeâ¯≈â¯1.00). Therefore, NIR chemometric modelling is a viable strategy to detect variability in PSD of excipients during blending and could enable real-time control of mixing. Most significantly, this strategy is potentially transferable to the monitoring and controlling of batch and continuous processes, where PSD is either a source of process variability or a critical quality attribute.
Assuntos
Composição de Medicamentos/métodos , Excipientes/química , Lactose/química , Celulose/química , Clorfeniramina/química , Análise dos Mínimos Quadrados , Tamanho da Partícula , Controle de Qualidade , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
Particle size distribution (PSD) variability in excipients is widely thought to affect the mixing process and the achievement of blend homogeneity. Yet, few studies have addressed this issue by attempting to ascertain the relationship and elucidate its mechanism. To address this, the model material, lactose, was modified to reflect commercially relevant PSD variations and mixed with microcrystalline cellulose and chlorpheniramine in a double-cone blender. Multivariate modelling and avalanche testing were applied to elucidate the relationship and mechanism. PSD variability can cause significant change in mixing time, by 8 times and 3 times (pâ¯≈â¯0.00) for high and low dose drug formulations, respectively. Achievement of blend homogeneity depended on the dispersive mixing mechanism (r2â¯=â¯0.99). Dispersive mixing was adversely affected by powder cohesiveness and powder dilation, which increased as the proportion of fine particles in lactose powder increased. This study yielded three conclusions. Firstly, PSD variability in pharmaceutical grade excipients can cause unacceptable prolongation in mixing time. Secondly, the impact of PSD variability on continuous mixing and other batch mixing of various scales, requires investigation. Lastly, the current findings can contribute to the development of robust mixing operations in the form of offline pre-emptive measures and inline process control strategies.
Assuntos
Composição de Medicamentos/métodos , Tamanho da Partícula , Celulose/química , Clorfeniramina/química , Excipientes/química , Lactose/química , Análise dos Mínimos Quadrados , Análise MultivariadaRESUMO
Extemporaneous oral preparations are routinely compounded in the pharmacy due to a lack of suitable formulations for special populations. Such small-scale pharmacy preparations also present an avenue for individualized pharmacotherapy. Orodispersible films (ODF) have increasingly been evaluated as a suitable dosage form for extemporaneous oral preparations. Nevertheless, as with all other extemporaneous preparations, safety and quality remain a concern. Although the United States Pharmacopeia (USP) recommends analytical testing of compounded preparations for quality assurance, pharmaceutical assays are typically not routinely performed for such non-sterile pharmacy preparations, due to the complexity and high cost of conventional assay methods such as high performance liquid chromatography (HPLC). Spectroscopic methods including Raman, infrared and near-infrared spectroscopy have been successfully applied as quality control tools in the industry. The state-of-art benchtop spectrometers used in those studies have the advantage of superior resolution and performance, but are not suitable for use in a small-scale pharmacy setting. In this study, we investigated the application of a miniaturized near infrared (NIR) spectrometer as a quality control tool for identification and quantification of drug content in extemporaneous ODFs. Miniaturized near infrared (NIR) spectroscopy is suitable for small-scale pharmacy applications in view of its small size, portability, simple user interface, rapid measurement and real-time prediction results. Nevertheless, the challenge with miniaturized NIR spectroscopy is its lower resolution compared to state-of-art benchtop equipment. We have successfully developed NIR spectroscopy calibration models for identification of ODFs containing five different drugs, and quantification of drug content in ODFs containing 2-10mg ondansetron (OND). The qualitative model for drug identification produced 100% prediction accuracy. The quantitative model to predict OND drug content in ODFs was divided into two calibrations for improved accuracy: Calibration I and II covered the 2-4mg and 4-10mg ranges respectively. Validation was performed for method accuracy, linearity and precision. In conclusion, this study demonstrates the feasibility of miniaturized NIR spectroscopy as a quality control tool for small-scale, pharmacy preparations. Due to its non-destructive nature, every dosage unit can be tested thus affording positive impact on patient safety.
Assuntos
Miniaturização , Preparações Farmacêuticas/química , Espectroscopia de Luz Próxima ao Infravermelho , Tecnologia Farmacêutica/métodos , Administração Oral , Calibragem , Clorfeniramina/química , Dexametasona/química , Formas de Dosagem , Composição de Medicamentos , Indometacina/química , Limite de Detecção , Nitrofurantoína/química , Ondansetron/química , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/normas , Análise de Componente Principal , Controle de Qualidade , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
First-line cancer chemotherapy necessitates high parenteral dosage and repeated dosing of a combination of drugs over a prolonged period. Current commercially available chemotherapeutic agents, such as Doxil and Taxol, are only capable of delivering single drug in a bolus dose. The aim of this study is to develop dual-drug-loaded, multilayered microparticles and to investigate their antitumor efficacy compared with single-drug-loaded particles. Results show hydrophilic doxorubicin HCl (DOX) and hydrophobic paclitaxel (PTX) localized in the poly(dl-lactic-co-glycolic acid, 50:50) (PLGA) shell and in the poly(l-lactic acid) (PLLA) core, respectively. The introduction of poly[(1,6-bis-carboxyphenoxy) hexane] (PCPH) into PLGA/PLLA microparticles causes PTX to be localized in the PLLA and PCPH mid-layers, whereas DOX is found in both the PLGA shell and core. PLGA/PLLA/PCPH microparticles with denser shells allow better control of DOX release. A delayed release of PTX is observed with the addition of PCPH. Three-dimensional MCF-7 spheroid studies demonstrate that controlled co-delivery of DOX and PTX from multilayered microparticles produces a greater reduction in spheroid growth rate compared with single-drug-loaded particles. This study provides mechanistic insights into how distinctive structure of multilayered microparticles can be designed to modulate the release profiles of anticancer drugs, and how co-delivery can potentially provide better antitumor response.
Assuntos
Microesferas , Polímeros/química , Esferoides Celulares/química , Antineoplásicos/química , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ácido Láctico/química , Células MCF-7 , Microscopia Confocal , Microscopia Eletrônica de Varredura , Polianidridos/química , Poliésteres , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Análise Espectral RamanRESUMO
Mechanical properties of collagen films are less than ideal for biomaterial development towards musculoskeletal repair or cardiovascular applications. Herein, we present a collagen-cellulose composite film (CCCF) compared against swine small intestine submucosa in regards to mechanical properties, cell growth, and histological analysis. CCCF was additionally characterized by FE-SEM, NMR, mass spectrometry, and Raman Microscopy to elucidate its physical structure, collagen-cellulose composition, and structure activity relationships. Mechanical properties of the CCCF were tested in both wet and dry environments, with anisotropic stress-strain curves that mimicked soft-tissue. Mesenchymal stem cells, human umbilical vein endothelial cells, and human coronary artery smooth muscle cells were able to proliferate on the collagen films with specific cell orientation. Mesenchymal stem cells had a higher proliferation index and were able to infiltrate CCCF to a higher degree than small intestine submucosa. With the underlying biological properties, we present a collagen-cellulose composite film towards forthcoming biomaterial-related applications.
Assuntos
Celulose/química , Colágeno/química , Tecido Conjuntivo , Membranas Artificiais , Células-Tronco Mesenquimais/fisiologia , Animais , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Células Cultivadas , Celulose/farmacologia , Colágeno/farmacologia , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Teste de Materiais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Nanofibras/química , Engenharia Tecidual/instrumentação , Engenharia Tecidual/métodos , Alicerces Teciduais/químicaRESUMO
Current focus on particulate drug delivery entails the need for increased drug loading and sustained release of water soluble drugs. Commonly studied biodegradable polyesters, such as poly(lactide-co-glycolide) (PLGA) and poly(l-lactide) (PLLA), are lacking in terms of loading efficiency of these drugs and a stable encapsulation environment for proteins. While hydrogels could enable higher loading of hydrophilic drugs, they are limited in terms of controlled and sustained release. With this in mind, the aim was to develop microparticles with a hydrophilic drug-loaded hydrogel core encapsulated within a biodegradable polyester shell that can improve hydrophilic drug loading, while providing controlled and sustained release. Herein, we report a single step method of fabricating microparticles via a concurrent ionotropic gelation and solvent extraction. Microparticles fabricated possess a core-shell structure of alginate, encapsulated in a shell constructed of either PLGA or PLLA. The cross-sectional morphology of particles was evaluated via scanning electron microscopy, calcium alginate core dissolution, FT-IR microscopy and Raman mapping. The incorporation of alginate within PLGA or PLLA was shown to increase encapsulation efficiency of a model hydrophilic drug metoclopramide HCl (MCA). The findings showed that the shell served as a membrane in controlling the release of drugs. Such gel-core hydrophobic-shell microparticles thus allow for improved loading and release of water soluble drugs.
RESUMO
With the increasing use of microfluidics, there is a need for a rather general experimental approach in order to monitor and characterize transport effects. Indeed, micro-fabrication methods have allowed the inclusion of numerous new structures and devices within microfluidics channels, and such alterations in flow patterns should impact solute transport characteristics. In the present contribution, Raman microscopy is combined with band-target entropy minimization analysis (BTEM) in order to rapidly assess and map concentration profiles in various regions of a microfluidics device. Two isotopomers, CHCl(3) and CDCl(3), are contacted under laminar conditions. Special consideration is given to the point of contact between the two liquids, transport in straight sections, transport in curved sections, and wall effects. Break-through curves confirmed that stagnation of fluid at the wall is not occurring, despite substantial wall roughness. Since the methods used in the present study are quite general, they should be useful in rapidly accessing transport effects when fluids (also in conjunction with colloids, suspensions, and solids) are contacted in the presence of both simple as well as complex geometries.
RESUMO
Double-layered microparticles, composed of poly(D,L-lactide-co-glycolide) (50:50) (PLGA) core and poly(L-lactide) (PLLA) shell, of controllable sizes ranging from several hundred microns to few microns were fabricated using a one-step solvent evaporation method. Metoclopramide monohydrochloride monohydrate (MCA), a hydrophilic drug, was selectively localized in the PLGA core. To achieve the double-layered particles of size approximately 2 µm, the process parameters were carefully manipulated to extend the phase separation time by increasing oil-to-water ratio and saturating the surrounding aqueous phase with solvent. Subsequently, the drug release profiles of the double-layered particles of various sizes were studied. Increased particle size resulted in faster degradation of polymers because of autocatalysis, accelerating the release rate of MCA. Interestingly, the effect of degradation rates, affected by particle sizes, on drug release was insignificant when the particle size was drastically reduced to 2-20 µm in the investigated double-layered particles. This understanding would provide critical insights into how the controllable formation and unique drug release profiles of double-layered particles of various sizes can be achieved.
Assuntos
Antieméticos/administração & dosagem , Preparações de Ação Retardada/química , Ácido Láctico/química , Metoclopramida/administração & dosagem , Poliésteres/química , Ácido Poliglicólico/química , Composição de Medicamentos/métodos , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido PoliglicólicoRESUMO
Triple-layered microparticles comprising poly(D,L-lactide-co-glycolide, 50:50) (PLGA), poly(L-lactide) (PLLA) and poly(ethylene-co-vinyl acetate, 40 wt.% vinyl acetate) (EVA) were fabricated using a one-step solvent evaporation technique, with ibuprofen drug localized in the EVA core. The aim of this study was to investigate the drug release profiles of these triple-layered microparticles in comparison to double-layered (PLLA/EVA and PLGA/EVA) (shell/core) and single-layered EVA microparticles. Double- and triple-layered microparticles were shown to eliminate burst release otherwise observed for single-layered microparticles. For triple-layered microparticles, the migration of acidic PGA oligomers from the PLGA shell accelerated the degradation of the PLLA mid-layer and subsequently enhanced drug release in comparison to double-layered PLLA/EVA microparticles. Further studies showed that drug release rates can be altered by changing the layer thicknesses of the triple-layered microparticles, and through specific tailoring of layer thicknesses, a zero-order release can be achieved. This study therefore provides important mechanistic insights into how the distinctive structural attributes of triple-layered microparticles can be tuned to control the drug release profiles.
Assuntos
Ibuprofeno/farmacocinética , Ácido Láctico , Poliésteres , Ácido Poliglicólico , Polivinil , Varredura Diferencial de Calorimetria , Cromatografia em Gel , Microscopia Eletrônica de Varredura , Peso Molecular , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Análise Espectral RamanRESUMO
This work reports how novel multi-layered (from double-layered to quadruple-layered) microparticles comprising immiscible polymers can be fabricated through a simple, economical, reliable and versatile one-step solvent evaporation method. These multi-layered microparticles would be excellent candidates to overcome problems inherent in single-layered microparticles for drug delivery. Particle morphologies, layer configurations, and drug distribution were determined by scanning electron microscopy and Raman mapping. Key process parameters achieving the formation of the multi-layered structure were identified. Encapsulation of multiple drugs and layer localization of these drugs within these multi-layered microparticles have also shown to be possible, which were driven by drug-polymer affinity. This one-step fabrication technique can therefore be used for tailoring particle designs, thus facilitating the development of multiparticulate drug delivery devices.
Assuntos
Microesferas , Polímeros/química , Cromatografia Líquida de Alta Pressão , Desenho de Fármacos , Microscopia Eletrônica de Varredura , Análise Espectral RamanRESUMO
Quantification of protein-polymer colocalization in a phase-separated polymer blend gives important insights into the protein release mechanism. Here, we report on the first visualization of protein-poly(ethylene glycol) (protein-PEG) colocalization in poly(ε-caprolactone)/poly(ethylene glycol) (PCL/PEG) blend films using a combined application of confocal Raman mapping and confocal laser scanning microscopy (CLSM) imaging. The degree of protein-PEG colocalization was further quantified via a novel image processing technique. This technique also allowed us to characterize the 3-D protein distribution within the films. Our results showed that the proteins were homogeneously distributed within the film matrix, independent of PEG content. However, the degree of protein-PEG colocalization was inversely proportional to PEG content, ranging from 65 to 94%. This quantitative data on protein-PEG colocalization was used along with in vitro PEG leaching profile to construct a predictive model for overall protein release. Our prediction matched well with the experimental protein release profile, which is characterized by an initial burst release and a subsequent slower diffusional release. More importantly, the success of this predictive model has highlighted the influence of protein-PEG colocalization on the protein release mechanism.
Assuntos
Portadores de Fármacos/química , Poliésteres/química , Polietilenoglicóis/química , Proteínas/químicaRESUMO
Hydrophobic, antirestenotic drugs such as paclitaxel (PCTX) and rapamycin are often incorporated into thin film coatings for local delivery using implantable medical devices and polymers such as drug-eluting stents and balloons. Selecting the optimum coating formulation through screening the release profile of these drugs in thin films is time consuming and labor intensive. We describe here a high-throughput assay utilizing three model hydrophobic fluorescent compounds: fluorescein diacetate (FDAc), coumarin-6, and rhodamine 6G that were incorporated into poly(d,l-lactide-co-glycolide) (PLGA) and PLGA-polyethylene glycol films. Raman microscopy determined the hydrophobic fluorescent dye distribution within the PLGA thin films in comparison with that of PCTX. Their subsequent release was screened in a high-throughput assay and directly compared with HPLC quantification of PCTX release. It was observed that PCTX controlled-release kinetics could be mimicked by a hydrophobic dye that had similar octanol-water partition coefficient values and homogeneous dissolution in a PLGA matrix as the drug. In particular, FDAc was found to be the optimal hydrophobic dye at modeling the burst release as well as the total amount of PCTX released over a period of 30 days.
Assuntos
Fármacos Cardiovasculares/química , Materiais Revestidos Biocompatíveis , Portadores de Fármacos , Corantes Fluorescentes/química , Ensaios de Triagem em Larga Escala , Ácido Láctico/química , Paclitaxel/química , Ácido Poliglicólico/química , Tecnologia Farmacêutica/métodos , Fármacos Cardiovasculares/administração & dosagem , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Cumarínicos/química , Preparações de Ação Retardada , Fluoresceínas/química , Interações Hidrofóbicas e Hidrofílicas , Cinética , Espectroscopia de Ressonância Magnética , Microscopia , Microscopia Eletrônica de Varredura , Estrutura Molecular , Paclitaxel/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Rodaminas/química , Solubilidade , Espectrometria de Fluorescência , Análise Espectral Raman , Propriedades de Superfície , Tiazóis/químicaRESUMO
Enhanced dissolution of poorly soluble active pharmaceutical ingredients (APIs) in amorphous solid dispersions often diminishes during storage due to moisture-induced re-crystallization. This study aims to investigate the influence of moisture protection on solid-state stability and dissolution profiles of melt-extruded fenofibrate (FF) and ketoconazole (KC) solid dispersions. Samples were kept in open, closed and Activ-vials(®) to control the moisture uptake under accelerated conditions. During 13-week storage, changes in API crystallinity were quantified using powder X-ray diffraction (PXRD) (Rietveld analysis) and high sensitivity differential scanning calorimetry (HSDSC) and compared with any change in dissolution profiles. Trace crystallinity was observed by Raman microscopy, which otherwise was undetected by PXRD and HSDSC. Results showed that while moisture protection was ineffective in preventing the re-crystallization of amorphous FF, KC remained X-ray amorphous despite 5% moisture uptake. Regardless of the degree of crystallinity increase in FF, the enhanced dissolution properties were similarly diminished. Moisture uptake above 10% in KC samples also led to re-crystallization and significant decrease in dissolution rates. In conclusion, eliminating moisture sorption may not be sufficient in ensuring the stability of solid dispersions. Analytical quantification of API crystallinity is crucial in detecting subtle increase in crystallinity that can diminish the enhanced dissolution properties of solid dispersions.
Assuntos
Inibidores de 14-alfa Desmetilase/química , Fenofibrato/química , Hipolipemiantes/química , Cetoconazol/química , Varredura Diferencial de Calorimetria/métodos , Cristalização , Estabilidade de Medicamentos , Umidade , Solubilidade , Análise Espectral Raman/métodos , Difração de Raios X/métodosRESUMO
Double-layered ternary-phase microparticles composed of a poly(D,L-lactide-co-glycolide) (50:50) (PLGA) core and a poly(L-lactide) (PLLA) shell impregnated with poly(caprolactone) (PCL) particulates were loaded with ibuprofen (IBU) and metoclopramide HCl (MCA) through a one-step fabrication process. MCA and IBU were localized in the PLGA core and in the shell, respectively. The aim of this study was to study the drug release profiles of these double-layered ternary-phase microparticles in comparison to binary-phase PLLA(shell)/PLGA(core) microparticles and neat microparticles. The particle morphologies, configurations and drug distributions were determined using scanning electron microscopy (SEM) and Raman mapping. The presence of PCL in the PLLA shell gave rise to an intermediate release rate of MCA between that of neat and binary-phase microparticles. The ternary-phase microparticles were also shown to have better controlled release of IBU than binary-phase microparticles. The drug release rates for MCA and IBU could be altered by changing the polymer mass ratios. Ternary-phase microparticles, therefore, provide more degrees of freedom in preparing microparticles with a variety of release profiles and kinetics.
Assuntos
Portadores de Fármacos/química , Ibuprofeno/química , Ácido Láctico/química , Metoclopramida/química , Poliésteres/química , Ácido Poliglicólico/química , Polímeros/química , Cromatografia em Gel , Composição de Medicamentos , Interações Hidrofóbicas e Hidrofílicas , Ibuprofeno/administração & dosagem , Metoclopramida/administração & dosagem , Microscopia Eletrônica de Varredura , Peso Molecular , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Solubilidade , Análise Espectral Raman , Propriedades de SuperfícieRESUMO
The aim of this study is to examine the physical mechanisms during the dissolution of a solid dispersion, so as to provide further understanding behind the enhanced dissolution properties. X-ray amorphous solid dispersions of ketoconazole (KC), a poorly aqueous soluble drug, were prepared by melt extrusion with polyvinlypyrrolidone 17 (PVP 17) and PVP-vinyl acetate (PVP-VA64) copolymer. Prior to dissolution, Raman mapping showed a fully homogeneous spatial distribution of KC in polymer and possible drug dispersion at molecular level, whereas Fourier transform infrared spectroscopy revealed no drug-polymer chemical interaction. During in vitro dissolution test, a burst release followed by a gradual decline in dissolution could be explained by the release of KC in molecular form followed by formation of drug nanoparticles and their subsequent growth to micron size range as shown by dynamic light scattering analysis. Observations using transmission electron microscopy and cryogenic scanning electron microscopy provided support to the suggested mechanisms. The results suggested that the release of KC from the solid dispersions was carrier controlled initially, and PVP 17 PF is more efficient in inhibiting particle growth as compared with PVP-VA64. The particle growth inhibition during dissolution may be an important consideration to achieve the full benefits of dissolution enhancement of solid dispersions.
Assuntos
Cetoconazol/química , Nanopartículas , Química Farmacêutica , Microscopia Crioeletrônica , Cristalização , Cristalografia por Raios X , Cinética , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Povidona/química , Difração de Pó , Pirrolidinas/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman , Tecnologia Farmacêutica/métodos , Compostos de Vinila/químicaRESUMO
Thin films of poly(lactic acid-co-glycolic acid) (PLGA) incorporating paclitaxel typically have slow release rates of paclitaxel of the order of 1 µg day(-1) cm(-2). For implementation as medical devices a range of zero order release rates (i.e. 1-15 µg day(-1) cm(-2)) is desirable for different tissues and pathologies. Eight and 35 kDa molecular weight polyethylene glycol (PEG) was incorporated at 15%, 25% and 50% weight ratios into PLGA containing 10 wt.% paclitaxel. The mechanical properties were assessed for potential use as medical implants and the rates of release of paclitaxel were quantified as per cent release and the more clinically useful rate of release in µg day(-1) cm(-2). Paclitaxel quantitation was correlated with the release of PEG from PLGA, to further understand its role in paclitaxel/PLGA release modulation. PEG release was found to correlate with paclitaxel release and the level of crystallinity of the PEG in the PLGA film, as measured by Raman spectrometry. This supports the concept of using a phase separating, partitioning compound to increase the release rates of hydrophobic drugs such as paclitaxel from PLGA films, where paclitaxel is normally homogeneously distributed/dissolved. Two formulations are promising for medical device thin films, when optimized for tensile strength, elongation, and drug release. For slow rates of paclitaxel release an average of 3.8 µg day(-1) cm(-2) using 15% 35k PEG for >30 days was achieved, while a high rate of drug release of 12 µg day(-1) cm(-2) was maintained using 25% 8 kDa PEG for up to 12 days.