Hot Melt Extrusion of Acrylic Films

Pharmaceutical Research -     

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.     

热熔挤出法制备槲皮素固体分散体

目的采用热熔挤出技术制备难溶性药物槲皮素的固体分散体,提高其溶出速率。方法以聚丙烯酸树脂(EudragitEPO)、聚维酮(PVP-K30)、共聚维酮(PVP-VA,Kollidon VA64)为亲水性载体材料,使用双螺杆热熔挤出机制备槲皮素固体分散体,通过体外溶出度测定、差示扫描量热法(DSC)、傅立叶红外光谱(FTIR)和X射线衍射法(XRD)来表征和评价所制备的固体分散体。结果制备的槲皮素固体分散体,与原料药相比,药物溶出得到显著提高,在人工胃液中3 min时处方槲皮素-EPO(1∶9)的药物溶出度可达到67%,处方槲皮素-木糖醇-PVPK30(1∶3∶6)的药物溶出度可达到65%,而在60 min时原料药溶出度不足10%。XRD图谱显示药物晶体衍射峰消失,DSC图谱显示药物熔点吸热峰消失,提示药物是以无定形态分散在载体材料中。结论热熔挤出技术可用于制备槲皮素固体分散体,使药物以无定型态高度分散在载体中,溶出度得到显著提高。     

熔融挤出法制备阿司匹林肠溶颗粒

目的 优化熔融挤出法制备阿司匹林肠溶颗粒的配方和方法.方法 以pH值1.2介质中耐酸性与pH值6.8介质中的溶出度为评价指标;以星点设计方法优选肠溶材料与辅料配比.结果 以79.8％醋酸羟丙甲纤维素琥珀酸酯为肠溶材料,4.2％十八醇为释药调节剂,3.0％微粉硅胶为润滑剂,于130℃下挤出,过程顺利,颗粒均一;所得载药颗...     

熔融挤出法制备尼莫地平缓释片

目的： 采用熔融挤出技术制备尼莫地平控释片。方法： 以PVPK30、PVPVA 64、PVPVA S-630 Poloxamer188-PVPK30(2:8)为载体,采用熔融挤出法制备不同质量比例的尼莫地平分散体,比较体外溶出度,并对利用X-射线粉末衍射(XRD)、扫描电镜(SEM)鉴别尼莫地平在载体中的状态。选取最优固体分散体,以羟丙甲纤维素(HPMC) 为骨架材料,制备尼莫地平控释片。结果： 以PVPVA 64为载体制备固体分散体,药物-载体比为 1:5时,1h累积溶出分别为98.5%。尼莫地平控释片体外持续释药12h以上,12h累积释药为97.1%,体外释药行为符合零级释药方程Q=0.0829t 0.0045(r=0.9988) 结论： 采用熔融挤出技术可以提高药物的体外溶出度,尼莫地平控释片处方合理,工艺稳定,具有长效的特点。     

Application of Melt Granulation Technology to Enhance Tabletting Properties of Poorly Compactible High-Dose Drugs

Using metformin HCl as the model drug and hydroxypropylcellulose (HPC) as the polymeric excipient, a melt granulation (MG) process that employs a twin-screw extruder has been developed to enhance compactibility of poorly compactible high-dose drug substances. A high (90%) drug-load tablet formulation, containing 1025 mg of active pharmaceutical ingredients and 109 mg of excipients, was produced. Drug–polymer–powder mixtures were melt granulated at a temperature above glass transition of HPC (130°C) but below melting point of metformin HCl (224°C). MG was compared with modified wet granulation (WG) and solvent granulation (SG) processes. Under identical compression force, the hardness of tablets produced was MG>SG>WG and the friability was MG<SG<WG. The hardness of WG tablets was highly sensitive to moisture content both during compression and subsequent storage, and, although not to the same extent, the hardness of SG tablets was also affected by loss-on-drying levels. MG provided a robust manufacturing process with highest compactibility and lowest friability that were not sensitive to changes in atmospheric moisture level. The process can decrease tablet sizes of high-dose drugs and combination products by decreasing the need for relatively large amounts of excipients generally used to overcome physicochemical limitations of drug substances.     

Hot Melt Extrusion and Spray Drying of Co-amorphous Indomethacin-Arginine With Polymers

Co-amorphous drug-amino acid systems have gained growing interest as an alternative to common amorphous formulations which contain polymers as stabilizers. Several preparation methods have recently been investigated, including vibrational ball milling on a laboratory scale or spray drying in a larger scale. In this study, the feasibility of hot melt extrusion for continuous manufacturing of co-amorphous drug-amino acid formulations was examined, challenging the fact that amino acids melt with degradation at high temperatures. Furthermore, the need for an addition of a polymer in this process was evaluated. After a polymer screening via the solvent evaporation method, co-amorphous indomethacin-arginine was prepared by a melting-solvent extrusion process without and with copovidone. The obtained products were characterized with respect to their solid-state properties, non-sink dissolution behavior, and stability. Results were compared to those of spray-dried formulations with the same compositions and to spray-dried indomethacin-copovidone. Overall, stable co-amorphous systems could be prepared by extrusion without or with copovidone, which exhibited comparable molecular interaction properties to the respective spray-dried products, while phase separation was detected by differential scanning calorimetry in several cases. The formulations containing indomethacin in combination with arginine and copovidone showed enhanced dissolution behavior over the formulations with only copovidone or arginine.     

热熔挤出技术制备伊曲康唑固体分散体及体外溶出考察

以羟丙甲纤维素(HPMC E5)为分散载体,利用热熔挤出技术制备难溶性药物伊曲康唑固体分散体,并探究不同挤出工艺参数和增塑剂1,2-丙二醇(PG)含量对固体分散体溶出度的影响。结果表明,二次挤出制得的固体分散体中药物的溶出率大于直接挤出的固体分散体,且二者均明显大于物理混合物。使用PG作增塑剂后伊曲康唑固体分散体的溶出率得到了显著提高,当PG用量较高(10%)时,固体分散体在0.1 mol/L盐酸介质中的溶出率可达到93%。本研究可以为热熔挤出的工艺开发提供更多的思路,同时为进一步制备高规格(200 mg)伊曲康唑片剂提供帮助。     

Hot Melt Extrusion as Solvent-Free Technique for a Continuous Manufacturing of Drug-Loaded Mesoporous Silica

The aim of this study is to explore hot melt extrusion (HME) as a solvent-free drug loading technique for preparation of stable amorphous solid dispersions using mesoporous silica (PSi). Ibuprofen and carvedilol were used as poorly soluble active pharmaceutical ingredients (APIs). Due to the high friction of an API:PSi mixture below the loading limit of the API, it was necessary to add the polymer Soluplus^® (SOL) in order to enable the extrusion process. As a result, the APIs were distributed between the PSi and SOL phase after HME. Due to its higher affinity to PSi, ibuprofen was mainly adsorbed into the PSi, whereas carvedilol was mainly found in the SOL phase. Intrinsic dissolution rate was highest for HME formulations, containing PSi, compared to pure crystalline (amorphous) APIs and HME formulations without PSi. HME is a feasible solvent-free drug loading technique for preparation of PSi-based amorphous solid dispersions.     

Polymorphic Transformation of Indomethacin during Hot Melt Extrusion Granulation: Process and Dissolution Control

Purpose

To study and elucidate the effect of the intensity and duration of processing stresses on the possible solid-state changes during a hot melt extrusion granulation process.

Methods

Blends of α-indomethacin and PEG 3350 (w/w 4:1) were granulated using various screw sizes/designs on the melt extruder under different temperature regimes. Differential Scanning Calorimetry and X-ray Powder Diffraction were employed for characterization. The dissolution behavior of the pure polymorphs and the resulting granules was determined using in-situ fiber optic UV testing system. An XRPD quantitation method using Excel full pattern fitting was developed to determine the concentration of each constituent (amorphous, α and γ indomethacin and PEG) in samples collected from each functioning zone and in granules.

Results

Analysis of in-process samples and granules revealed that higher temperature (≥130°C) and shear stress accelerated the process induced phase transitions from amorphous and/or the α form to γ indomethacin during heating stage. However, rapid cooling resulted in an increased percentage of the α form allowing isolation of the meta-stable form.

Conclusions

By determining the conditions that either prevent or facilitate process induced transformations of IMC polymorphs during melt granulation, a design space was developed to control the polymorph present in the resulting granules. This represents the conditions necessary to balance the thermodynamic relationships between the polymorphs of the IMC system and the kinetics of the possible transformations as a function of the processing stresses.

     

Drug Solubilization by Means of a Surface-Modified Edible Biopolymer Enabled by Hot Melt Extrusion

A coprocessing/formulation approach for increasing the solubility of poorly soluble drugs using solid dispersions is presented, whereby the active pharmaceutical ingredients (API) retains its crystalline state. The approach uses a biopolymer naturally produced as dendrimeric nanoparticles that has been surface-modified to act as a solubilizing agent. The solubilizing agent is enabled by hot melt extrusion to produce the solid dispersions. Four APIs, phenytoin (PHT), griseofulvin, ibuprofen, and loratadine were used as model compounds to evaluate solubility enhancement. The rank order in solubility enhancement follows that of the hydrophobicity of the APIs. The APIs remained predominantly crystalline after hot melt extrusion processing. However, APIs with weak crystal structure (ibuprofen and loratadine) underwent measurable crystallinity loss. The solubilizing power of the modified biopolymer increases with increasing hydrophobicity and strength of the crystal structure. The solubility is described in terms of a parallel liquid-phase partition-association. For one API (PHT), solubility enhancement was minimal. The dissimilar behavior of PHT is discussed in terms of the polarity match between the API and the hydrophobic microenvironment in the solubilizing agent. This approach is expected to apply to a large number of poorly soluble drugs, offering a complementary approach to existing processing and formulation drug solubilization methods.     

Formulation and Evaluation of Sustained Release Extrudes Prepared via Novel Hot Melt Extrusion Technique

The purpose of the present investigation is to emphasize the application of hot-melt extrusion technique (HMET) for the preparation of sustained release matrix formulation of highly dosed, freely soluble drugs. In this study, sustained release multiple unit dosage of venlafaxine hydrochloride (VH) was prepared by HMET. Custom design was used to screen the effect of four factors-type of polymer (ethylcellulose and eudragit RSPO) (X ₁), amount of polymer (X ₂), type of plasticizer (DBS, ATBC, TEC, and PEG) (X ₃), and plasticizer concentration (X ₄), on the drug release at 8 h (Y1) and machine torque (Y2). The experiments were carried out according to a four-factor 16-run statistical model and subjected to 12-h dissolution study in purified water. The significance of the model was indicated by ANOVA. Results of in vitro release study indicate that formulations prepared with higher amount of ethylcellulose and DBC show significant retardation at 8 h. The result shows that increase in concentration of polymer with the combination of water insoluble plasticizer (DBS and ATBC) has better sustained release while increasing concentration of TEC and PEG results faster in vitro release. Besides that increase in plasticizer concentration helps in reducing the melt temperature and machine torque. The in vivo study was performed, and formulations were compared using area under the plasma concentration-time curve (AUC_0-∞), time to reach peak plasma concentration (T_max), and peak plasma concentration (C_max). The drug release profiles of extrudes were found to fit both diffusion and surface erosion models. Further to this, scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction analysis of the hot-melt extrudates demonstrated that VH remained crystalline and was homogeneously dispersed throughout the polymer matrix.     

Characterization of Solid Dispersions of Itraconazole and Hydroxypropylmethylcellulose Prepared by Melt Extrusion,Part II

Purpose. This study was done to elucidate the physical and pharmaceutical properties of itraconazole-HPMC dispersions and the influence of water on the phase separation. Methods. Extrudates were prepared using a corotating twin-screw hot-stage extruder with fixed process parameters. Modulated-temperature differential scanning calorimetry (MTDSC) and DSC 111 were used to examine the mixing behavior of itraconazole and the carrier by evaluation of the glass transition region. High temperature diffuse reflectance infrared transform spectroscopy (HT-DRIFT) was performed to reveal interactions between itraconazole and HPMC. Dissolution was performed to investigate the pharmaceutical performance of the dispersions. Results. Although the dissolution rate of itraconazole significantly increased, we found that the solid dispersions do not form a homogeneous system. A different picture was obtained depending on the way MTDSC analysis was performed, i.e., using open or closed sample pans. Water can evaporate in open pans, which allows itraconazole to interact with HPMC and leads to a partially mixed phase. Analysis in hermetically closed pans revealed a further phase separation as water remains on the sample and impedes the interaction between drug and polymer. Conclusions. Solid dispersions of itraconazole and HPMC do not form a homogeneous phase.     

葛根素-壳寡糖共无定型制备与体外溶出度评价

目的 提高葛根素的生物利用度.方法 采用低温研磨法制备葛根素-壳寡糖共无定型(PUE-COS CM),采用差示扫描量热法、X射线粉末衍射法、傅里叶红外光谱法、扫描电镜法对PUE-COS CM进行固态表征分析;评价PUE-COS CM在漏槽和非漏槽2种条件下的体外溶出行为,并考察其稳定性.结果 差示扫描量热法证实,PUE...     

Improving the Chemical Stability of Amorphous Solid Dispersion with Cocrystal Technique by Hot Melt Extrusion

Purpose  

To explore in-situ forming cocrystal as a single-step, efficient method to significantly depress the processing temperature and thus minimize the thermal degradation of heat-sensitive drug in preparation of solid dispersions by melting method (MM) and hot melt extrusion (HME).     

Potential Determinants of Prescribers' Drug-Drug Interaction Knowledge

BackgroundHealth care professionals' ability to recognize potential drug-drug interactions (potential DDIs) is important in reducing the risk of potential DDIs and their adverse consequences. Until now, little is known about the determinants of prescribers' potential DDI knowledge.ObjectivesThis study was conducted to develop interval scales to evaluate prescribers' potential DDI knowledge and perceived usefulness of various potential DDI information sources, and to examine demographic and practice factors that may be related to prescribers' knowledge of potential DDIs.MethodsData were obtained from a national mail survey of prescribers who were determined from pharmacy claims obtained from a pharmacy benefits manager to have prescribed at least 1 drug involved in a potential DDI, and a control group who had prescribed either 1 of the medications in the drug combinations of interest. The survey instrument included 14 drug-drug pairs that evaluated prescribers' ability to recognize clinically important potential DDIs and 5-point Likert scale-type questions that assessed prescribers' perceived usefulness of potential DDI information provided by various sources. The knowledge and usefulness questions were examined via Rasch dichotomous and rating scale models, respectively.ResultsA total of 950 completed surveys were included in the analysis (overall adjusted response rate: 7.9%). Rasch analysis of knowledge and usefulness items revealed satisfactory model-data-fit (infit mean square [MNSQ] ≦ 1.5 and outfit MNSQ ≦ 2.0) and moderate person reliability of 0.72 and 0.61, respectively. Multiple regression analysis revealed that compared with generalists, specialists had lower potential DDI knowledge test scores. In addition, poorer potential DDI knowledge was associated with a lack of clinical experience witnessing harm caused by a potential DDI. Also, the prescribers whose drug selections were affected by the risk of potential DDIs “very much” scored higher than those who reported that their prescribing was affected by the risk “a little” or “not at all.”ConclusionsThis study found that specialists were less likely to correctly identify interactions compared with generalists. Other important predictors of potential DDI knowledge included the experience of seeing a potential DDI-caused harm and the extent to which the risk of potential DDIs affected prescribers' drug selection.     

Drug-Drug Interaction Studies on First-Line Anti-tuberculosis Drugs

The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40°C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%–5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%–95% and 70%–75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner.