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Welcome to Quadra Ingredients Fall Webinar Series
Our 5th session in our new webinar series will be held on Wednesday October 21st @ 2 pm EST. We will be featuring Nisso HPC, our supply partner for the Canadian Pharma and Supplement markets and the US Pharma markets.
Join us as Dr. Edmont Stoyanov presents &#; HPC advantages compared to HPMC for Sustained Release Matrix Tablets
Nisso HPC (hydroxypropyl cellulose) is available in high-molecular weight, fine powder grades designed for direct compression sustained release tablets. These hydrophilic matrix tablets can be formulated to control drug release from 4 to 24 hours.
Compared to HPMC, tablets made with HPC are:
easier to manufacture with lower compression force
more robust and less variable in-vitro and in-vivo
Non-GMO Project Verified for customer friendliness
This webinar will present case studies and formulation recommendations
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Using polymers as additives to formulate ternary amorphous solid dispersions (ASDs) has successfully been established to increase the bioavailability of poorly soluble drugs, when one polymer is not able to provide both, stabilizing the drug in the matrix and the supersaturated solution. Therefore, we investigated the influence of low-viscosity hydroxypropyl cellulose (HPC) polymers as an additive in HPMC based ternary ASD formulations made by hot-melt extrusion (HME) on the bioavailability of itraconazole (ITZ). The partitioning potential of the different HPC grades was screened in biphasic supersaturation assays. Solid-state analytics were performed using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD). The addition of HPCs, especially HPC-UL, resulted in a superior partitioned amount of ITZ in biphasic supersaturation assays. Moreover, the approach in using HPCs as an additive in HPMC based ASDs led to an increase in partitioned ITZ compared to Sporanox® in biorelevant biphasic dissolution studies. The results from the biphasic dissolution experiments correlated well with the in vivo studies, which revealed the highest oral bioavailability for the ternary ASD comprising HPC-UL and HPMC.
Hydroxypropyl cellulose (HPC) is a polymeric excipient which has been used as functional additive in ternary ASDs. HPC is a semisynthetic cellulose ether ( ) in which the hydroxyl groups of the cellulose backbone are additionally hydroxypropylated ( Zhou et al., ). It is available in various chain lengths. In general, HPC is capable to stabilize supersaturated states of several APIs enabled by its precipitation inhibitory potential ( Curatolo et al., ; Megrab et al., ). Due to its melt viscosity and thermal stability, HPC is also suitable as a polymeric carrier for the preparation of ASDs by means of hot-melt extrusion (HME) ( Paradkar et al., ; Vasconcelos et al., ). However, the low glass transition temperature (T g ) of low-viscosity HPCs (&#;25&#;0 °C) ( Sarode et al., ) make those a less favorable matrix polymer for ASDs as inferior physical stability compared to HPMC, HPMCAS or copovidone can be expected. As an additive in ternary ASDs, HPC-SSL was successfully used in combination with HPMCAS as the main polymeric carrier to moderate the supersaturation of dipyridamole throughout the entire GI tract ( Zecevic et al., ).
Due to the fact that one polymer is not always capable to provide both, sufficient physical stabilization of the amorphous active pharmaceutical ingredient (API) and stabilization of the supersaturated solution upon dissolution, we previously proved the benefit to introduce an additional excipient to binary ASDs. The so called multicomponent ASDs such as ternary ASDs can thus further improve the dissolution performance and physical stability of poorly soluble drugs by rational selection of suitable polymer/excipient combinations ( Prasad et al., ; Six et al., ; Yoo et al., ). The addition of a third component shall improve the physical stability and/or promote the dissolution by the inhibition of drug recrystallization ( Baghel et al., b ).
The maximum plasma concentration (c max ) and the associated time t max were determined directly from the plasma concentration profiles. The determination of the area under the curve (AUC) of the plasma concentration profiles were estimated by trapezoidal integration to the last sampling point (24 h). The evaluation of the bioavailability was performed by using the sum of the AUCs of ITZ and OH-ITZ (AUC sum ). The statistical comparison of c max and AUC ITZ were accomplished with a one-way analysis of variance (ANOVA) and post hoc Tukey's multiple comparison test. P values of <0.05 were considered as statistically significant.
The quantification of ITZ and OH-ITZ (the major active metabolite of ITZ in humans ( Heykants et al., ) as well as in rats ( Yoo et al., )) was performed for all plasma samples. For the bioanalytics, a Waters e Separation Module coupled to a Waters ACQ-QDA Detector was used. MS-measurements were performed with a capillary voltage of 0.8 kV and a cone voltage of 15 V. A Waters XBridge® Shield RP18 column (3.5 μm, 2.1 mm × 100 mm, 130 Å) was installed and the column temperature set to 30 °C. Non-isocratic conditions were applied to measure the ITZ and OH-ITZ plasma concentrations precisely. The compositions of the mobile phases and the non-isocratic conditions are described in , . For detection, the positive ion electrospray ionization mode was used. Quantification was performed with an internal standard method using KTZ as the internal standard.
20 μl of plasma was added into an Eppendorf tube. After addition of 20 μl of an internal standard solution (containing ng/ml KTZ in AcN) and 40 μl of ice-cold AcN, the Eppendorf tubes were vortexed for 60 s and centrifuged (25 min, 11,000 rpm, 4 °C) using a ThermoFischer Heraeus Fresco 17 centrifuge (Thermo Electron LED GmbH, Osterode, Germany). The supernatant was then transferred into LC vials (Waters Screw Neck Total Recovery Vials, Eschborn, Germany) and analyzed by LC-MS as described in the next section. The same procedure was performed for the calibration. A certain amount of calibration stock solution was diluted by centrifuged plasma (from purchased raw rat blood) 20-fold and underwent the same plasma extraction procedure as the collected plasma samples.
Each formulation was dosed orally equal to 5 mg of ITZ, as either Sporanox® pellets or ASDs, dispersed in 500 μl water. All formulations were dosed via an oral gavage. Blood samples of 300 μl were collected by individual venipunctures of the lateral tail vein after 1, 2, 3, 4, 6, 8, 10 and 24 h after and 0.5 h before the formulation application in lithium heparinized centrifugation tubes (25 I.U./ml, 1.3 ml, Sarstedt AG & Co. KG, Nümbruch, Germany). To obtain plasma, the blood samples were centrifuged (g, 4 °C, 10 min) using a ThermoFischer Heraeus Multifuge X1 (Thermo Electron LED GmbH, Osterode, Germany) and kept frozen at &#;70 °C until further preparation and analysis by LC-MS.
For in vivo studies, the three formulations Sporanox®, ITZ:HPC-UL:HPMC 1:3:6 HME and ITZ:HPC-SSL:HPMC 1:3:6 HME were tested each on three male Sprague-Dawley rats (280&#;350 g, approx. 9 weeks of age). All animal experiments were conducted according to the European Union Directive /63/EU. Those studies were performed at the University of Bourgogne Franche-Comté (Besancon, France) in compliance with the French legislation and European Community Guidelines on animal experimentation under the authorization number &#;Project Exp An N2 EA -&#;, accepted by the ethical committee CEBEA 58. The animals were acclimatized for one week and fasted for 12 h before the application with constant access to water. After application of the formulations (t = 0), food was rearranged.
An amount equivalent to 5 mg of ITZ was used for the studies. In case of Sporanox®, the capsules were opened and an amount equivalent to 5 mg ITZ was withdrawn and used for biorelevant biphasic dissolution. The partitioned amount of ITZ in the absorptive sink at the last time point was statistically compared by using the one-way analysis of variance (ANOVA) and a post hoc Tukey's multiple comparison test.
Sporanox® and the ASDs of ITZ with Affinisol® HME15LV (HPMC) and HPC-UL/HPC-SSL (ITZ:HPC-UL/-SSL:HPMC 1:3:6) were tested in biphasic dissolution studies. The same apparatus and conditions were used as for the biphasic supersaturation studies (2.2.). Instead of polymeric solutions, pure 0.1 N HCl solution was used for the starting medium of pH 1.0. The duration time was set to 60 min at pH 1.0, 45 min at pH 5.5 and 90 min at pH 6.8.
A co-rotating 12 mm twin-screw extruder ZE 12 from Three-Tec GmbH (Seon, Switzerland) with a functional length of 25:1 L/D and a 2 mm die was used for the preparation of the ternary ASDs. The composition of the formulations and the extruder conditions and properties are described in . The feed rate was set to 2 g/min. The composition of the ternary ASDs was determined based on preliminary studies. HPC alone is not suitable to create single phased systems containing ITZ. However, HPMC (shown on Sporanox®) is suitable to incorporate ITZ within its polymeric matrix. Thus, different mixtures of HPC and HPMC were prepared with ITZ in order to make transparent films via film casting. The ratio of 1:2 (HPC:HPMC) was suitable to produce transparent films, indicating a single phased ASD. The extrusion temperature was chosen based on the HPMC supplier's recommendation. The screw speed and feed rate was adopted according to previous publications ( Monschke et al., ; Monschke and Wagner, ; Monschke and Wagner, ).
In order to investigate the partitioning rate of ITZ in presence of the different HPC grades, biphasic supersaturation studies were performed using the BiPHa+ apparatus developed by Denninger et al. ( Denninger et al., ). The apparatus mainly consists of four cylindrical vessels (one blank and three sample vessels) set into a water bath with a temperature of 37 ± 0.5 °C. These vessels were each filled with 50.0 ml of the aqueous phase. For generation of the aqueous phase, each HPC grade was previously dissolved in 0.1 N HCl solution to obtain polymer concentrations of 0.250% (w/v), 0.125% (w/v) and 0.063% (w/v). Furthermore, triangular magnetic stirrer were put into the vessels at 170 rpm to gain sufficient hydrodynamics. The biorelevant biphasic supersaturation studies were divided into three pH stages. The steps were: 15 min at pH 1.0, 45 min at pH 5.5 and 90 min at pH 6.8. The pH shifts were conducted by the use of a concentrated citrate-phosphate buffer. The pH was monitored during the whole experiments. An ITZ stock solution (10 mg/ml) in DMSO was added to 50 ml of each prepared vessel by targeting a concentration of 0.1 mg/ml of ITZ. Immediately prior the pH adjustment to 5.5, a stock solution of sodium taurocholate and lecithin was added to the aqueous phase to obtain a fasted state simulated intestinal fluid (FaSSIF)-V2 like biorelevant medium ( Denninger et al., ). Subsequently, 50.0 ml of 1-decanol were added to create the absorptive sink medium. Both, the adjustment of the pH and addition of the absorptive sink, were performed by a fully automated liquid dispenser. For the quantification of the ITZ concentration in the aqueous phase and the absorptive sink, an Agilent diode array UV spectrophotometer was used.
The model drug itraconazole (ITZ) was obtained from Sris Pharmaceuticals (Hyderabad, India). Hydroxy-itraconazole (OH-ITZ, 0.1 mg/ml methanol solution), the major active metabolite of ITZ in rats ( Yoo et al., ) as well as in humans ( Heykants et al., ), was obtained from Sigma-Aldrich (Taufkirchen, Germany). Ketoconazole (KTZ), the internal standard, was obtained from ThermoFisher (Kandel, Germany). Sporanox® 100 mg capsules were obtained from Janssen GmbH (Neuss, Germany). HPC-SL (M W = 100,000 g/mol; 73.5% Hydroxypropoxy groups), -SSL (M W = 40,000 g/mol; 73.7% Hydroxypropoxy groups) and -UL (M W = 20,000 g/mol; 70.1% Hydroxypropoxy groups) were kindly donated by Nippon Soda Co., Ltd. (Tokyo, Japan). Affinisol® HME15LV (HPMC) was donated from Dow Chemical Company, (Bomlitz, Germany). LC-MS grade water was obtained from Bernd Kraft GmbH (Duisburg, Germany). LC-MS grade acetonitrile (AcN), potassium citrate monohydrate (> 99%) were obtained from VWR Chemicals GmbH (Darmstadt, Germany). Lecithin, sodium taurocholate, 1-decanol and potassium phosphate were obtained from ThermoFisher (Kandel, Germany). Sodium hydroxide was obtained from Honeywell Fluka (Seelze, Germany). 0.1 N HCl solutions were obtained from VWR Chemicals (Fontenay-sous-Bois, France). Dimethyl sulfoxide (DMSO, > 99.9%) was obtained from Fisher Scientific (Geel, Belgium).
The results of the biphasic supersaturation assays are provided in . At pH 1.0, ITZ completely remained in solution after it was added in form of DMSO stock solutions, independent on the presence or absence of an HPC polymer. Continued with the first pH shift and the addition of the FaSSIF-V2 concentrate, ITZ started to precipitate in all cases resulting in a cloudy aqueous suspension with visible precipitates related to the change of ITZ from a positively charged species into an uncharged (Peeters et al., ). For the period between 45 and 60 min, the presence of the different HPC polymers led to a concentration of approx. 1&#;3% ITZ in the aqueous phase. After that, the dissolved amount of ITZ in the aqueous phase dropped to approx. 0.8% and the ITZ partitioning rate into the absorption sink was reduced independent on the tested polymer and the tested polymer concentration. Despite the fact, that there was no significant difference among all tested samples regarding the ITZ concentration in the aqueous phase after the pH shift, the partitioned amount of ITZ into the organic solvent layer clearly differed. By increasing the concentration of each HPC polymer, the partitioned amount of ITZ was increased and the difference between the HPC grades was less pronounced. The presence of all tested HPC grades, however, significantly increased the partitioned amount of ITZ into the absorption sink regardless of the polymer concentration compared to pure ITZ. Only HPC-SL at a concentration of 0.063% (w/v) did not result in a significant higher concentration compared to the pure ITZ. The presence of HPC-UL resulted in the fastest partitioning rate and thus for all concentrations in the highest partitioned amount of ITZ, respectively (0.063% (w/v): 6.17% ITZ; 0.125% (w/v): 7.65% ITZ; 0.250% (w/v): 9.19% ITZ, after 150 min, ). HPC-UL resulted at all concentrations except for 0.063% (w/v) in a significant higher distribution of ITZ than HPC-SSL. At polymer concentrations of at least 0.125% (w/v) a rank order of UL > SSL > SL in terms of ITZ partitioning was observed ( ). The lower molecular weight HPC polymer HPC-UL exhibited the greatest effect on promoting the partitioning of ITZ. In all cases, the partitioning rate of ITZ into the absorption sink decreased after approx. 60 min after the pH shift, likely due to the further concentration reduction caused by the second pH-shift to pH 6.8.
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HPC polymers have been successfully tested in the past in stabilizing the supersaturation of poorly soluble drugs with different physicochemical properties e.g. ibuprofen, carbamazepine, phenytoin and chlorphenamine (Sarode et al., ; Terebetski et al., ). Furthermore, it was also shown, that an HPC-SSL based formulation promoted the partitioning of felodipine in the n-octanol layer during biphasic dissolution assays compared to the neat API (Sarode et al., ). The ITZ concentrations in the aqueous phase were too low to distinguish the effect of the HPC polymers with regard to supersaturation, whereas significant differences in the organic solvent layer might be related to enhanced re-dissolution kinetics of the precipitated particles (Frank et al., ). This phenomenon was also reported during the biphasic dissolution studies of ritonavir under biorelevant conditions (Denninger et al., ).
shows the solid-state analytics of all formulations. Main peaks of ITZ are clearly shown at 14.5° 2θ, 17.5° 2θ, 18.0° 2θ, 20.4° 2θ. 23.5° 2θ, 25.5° 2θ and 27.1° 2θ for the neat substance as well as the physical mixtures. The comparison between the HME processed components and their physical mixtures showed, that ITZ was amorphous within the solid dispersions by showing a diffuse halo with no Bragg peaks of ITZ in the XRPD diffractograms. After 6 months under stability conditions, the solid-state of the ASDs did not change, indicating an acceptable physical stability. Minor peaks in the diffractograms of the ternary ASDs shown at approx. 32° 2θ can be explained by the presence of residual sodium chloride during the manufacturing process of Affinisol® HME15LV. The DSC thermograms revealed a glass transition temperature at 70.5 °C for ITZ:HPMC:HPC-UL 1:6:3 ASD and at 72.7 °C for the ITZ:HPMC:HPC-SSL 1:6:3 ASD. The presence of one single glass transition temperature and the absence of a melting endotherm indicated single phased ASDs.
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shows the in vitro biphasic dissolution tests of the ternary ASDs in comparison to Sporanox®. All ternary ASDs dissolved completely within the first 60 min under acidic conditions ( A). The solid-state analytics revealed single-phase systems which proved that ITZ was molecularly dispersed within the polymeric carrier. Hence, the dissolution rate of ITZ was controlled by the dissolution rate of HPMC and HPC-UL or -SSL. It is worth mentioning that ITZ:HPC-UL:HPMC 1:3:6 HME dissolved faster than the SSL formulation as a lower molecular weight increased the dissolution kinetics of the ASD polymer (Sarode et al., ).
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Both ternary ASDs exhibited a faster dissolution rate compared to Sporanox® within the first 15 min. Due to the fact, that the formulations were already dissolved before the pH shifted and precipitated prior the addition of 1-decanol, the dissolution rates of the formulations did not have an influence on the partitioning rate of ITZ into the organic phase. However, the presence of the HPC polymers affected the partitioned amount of ITZ, despite the fact, that there were no significant differences in the aqueous phase. Sporanox® partitioned approximately 5.5% of ITZ into the organic layer after 195 min. In comparison, both ternary ASDs resulted in significant higher partitioned ITZ into the organic solvent layer. The ITZ:HPC-UL:HPMC ASD partitioned 8.33% (p < 0.05) compared to Sporanox® (5.56%) into the 1-decanol phase ( , B + C), while the dissolution test of the ASDs containing HPC-SSL resulted in a partitioned amount of 7.48% ITZ (p < 0.1 compared to Sporanox®. It was shown, that HPMC is capable of stabilizing supersaturated ITZ solutions (Verreck et al., ). An addition of different HPC grades, however, showed no difference in the aqueous phase within the biphasic supersaturation assays as a consequence of the extremely low solubility of ITZ at pH values above its pKa. However, the addition of HPC-SSL and especially HPC-UL promoted the partitioning rate of ITZ into the organic solvent layer, even in combination with HPMC. This might be related to faster re-dissolution kinetics of the precipitate, facilitated by the presence of HPC (Frank et al., ; Xie et al., ). Denninger et al. () showed that the transition into the organic phase could be of significant difference despite the fact that the aqueous concentration was on the same level. They revealed that the difference in partitioning rate was related to the re-dissolution kinetics of the precipitate.
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When extruding blends of metformin HCl and HPC GXF with screw configuration SC#1, a higher extruder torque was observed, ranging from 8&#;12%. Higher extrusion temperatures of 160 and 140 °C showed a higher operating torque than the lower temperatures 120 and 100 °C. In the case of HPMC HME 4M, a torque of 4&#;6% was only observed when extruding at 160 °C with screw configuration SC#1. Extrusion at 100, 120 and 140 °C showed minimum extruder torque (&#;3%) during the process. When the screw configuration was changed to a lower shear screw configuration SC#2, the torque remained around 8&#;12% in the case of HPC GXF, whereas melt granulation with HPMC HME 4M showed a minimum extruder torque at all temperatures. Extruder torque is an indication of the force the motor exerts to move the screws to push the material forward. A higher extruder torque in melt granulation sometimes indicates a better agglomeration or compaction of material into dense granules.
Two different screw configurations were used for this study, as shown in Figure 1 . Screw configuration#2 provided moderate shear to the powder, with mixing elements rotating at 60°. Screw configuration#1, with mixing elements rotating at 90°, provided higher shear to the material. Blends were melt granulated at four processing temperatures of 160, 140, 120 and 100 °C using a powder feed rate of 20 g/min and screw speed of 100 rpm. The extrusion temperature and screw configuration were changed and the effect of these two process variables on granule properties was studied. Different temperature profiles used for this study are shown in Table 2
Care was taken to avoid the possibility that the exposure to high shear provided by screw configuration and feed rate could lead to a complete or partial melting of a drug at relatively high temperature. In this case, because the melted drug may also contribute to granulation, any melting of a drug will make it difficult to distinguish between the effects of the melted drug and polymer. To avoid such a situation, only API (metformin hydrochloride) was first passed through the barrel using specific temperature profiles, feed rates, screw configurations, and screw speeds planned for subsequent twin-screw melt granulation experiments. Screw shafts were then pulled out of the barrel. Both screw shafts, as well as the extruder barrel, were examined for any charring or the presence of molten, viscous material which could indicate the possible melting of the drug. If charring or the presence of molten material was observed, those process conditions were eliminated from any future experiments. Usually, the extrusion temperature is kept 30&#;40 °C below the melting point of the drug. Our initial temperature profile, based on preliminary experiments with HPMC HME 4M and metformin HCl, showed that the drug partially melted at the temperature of 180 °C. Therefore, the extrusion temperature of 180 °C was removed from the experimental design and a maximum extrusion temperature of 160 °C was used for all experiments. A feed rate of 20 g/min and screw speed of 100 rpm was kept constant for all experiments.
Different process variables can impact the final product characteristics in a melt granulation process. These process variables include screw speed, powder feed rate, screw configuration, and temperature profile. The granule properties may be impacted by high or low shear in the extruder barrel. The shear in the extruder barrel (at a specific extrusion temperature) can be varied by changing the screw speed and/or powder feed rate. An increase in feed rate and screw speed may increase the mechanical shear inside the extruder barrel to improve binding and agglomeration, and thus increase the granulation tendency of the polymer.
Using the minimum quantity of rate-controlling polymers in formulations, where the controlled release of a highly soluble, high-dose active is desired, is a major challenge for formulators. Twin-screw melt granulation can enable a formulator to use minimal amounts of these polymers to obtain controlled- or extended-release formulations of highly soluble actives. The concentration of a polymer in a melt granulation may vary from 10&#;30%depending on the desired drug release pattern. Some authors showed that the successful melt granulation of metformin HCl can be carried out even with a low concentration of polymers (<10%) [ 27 ]. These reports, however, targeted the immediate release of metformin HCl. From our experience, a polymer concentration minimum of 15&#;25%is required to obtain a controlled drug release with high-molecular-weight HPC and HPMC. Therefore, blends of 75%metformin HCl and 25%polymer were prepared for melt granulation.
In the case of HPMC HME 4M, when the processing temperature was varied from 100 °C to 160 °C, HPMC HME 4M granule quality showed a significant variability, as shown in Figure 2 b. For HPMC HME 4M, granules were only obtained at 160 °C. At lower temperatures, the polymer did not fully melt, yielding a fine powder and granules of an irregular nature. Nonetheless, it was anticipated that granules obtained with HPMC HME 4M may still provide adequate tablet strength. When the screw configuration was changed to a lower shear, SC#2, fine particles were obtained at all temperatures. There was no change in the appearance of the melt-granulated particles in the feed blend. This showed that HPMC HME 4M required a higher shear in the extruder to melt, and a low shear screw configuration was inadequate for providing shear to the polymer for melting and granulation.
In twin-screw melt granulation, process conditions, as well as the melt viscosity of the binder, can impact the granule properties. Using screw configuration SC#1 for the extrusion of HPC GXF, granule shape and appearance were affected when the processing temperature was varied from 100 to 160 °C, as shown in Figure 2 a. At a lower processing temperature of 100 °C, the granules were hard agglomerates (centimeter), but smaller in size. As the temperature was increased from 100 to 120 °C, the granule morphology changed to more ribbon-like granules. At higher temperatures of 140 and 160 °C, the granules produced were more consistently continuous and ribbon-shaped. The granule morphology indicated that, at higher temperatures, HPC had a lower melt viscosity and increased binding capacity to bind and agglomerate metformin HCl to produce ribbon-shaped granules. It was apparent that these granules or extrudates were to be milled to produce smaller particles that could provide an acceptable flow for tableting. When the screw configuration was changed to a low shear SC#1, no significant change in granule morphology was observed. Ribbon-like extrudates were obtained at high temperatures of 140 and 160 °C and hard agglomerates were obtained at 100 and 120 °C.
In the case of HPMC HME 4M, milled granules obtained at 100, 120 and 140 °C with screw configuration SC#1 simply passed through the screen during milling. When this powder was analyzed using sieve analysis, most of the particles (>98%) in these samples were <125 µm. Granules obtained at 160 °C also passed through the screen without any potential milling. When these granules were analyzed using sieve analysis for particle size distribution, these powders had a lower number of fines (<125 µm). The particle size distribution of milled granules obtained at 140 and 160 °C with HPC GXF and HPMC HME 4M is shown in Table 3 . When melt-granulated samples of metformin HCl and HPMC HME 4M, obtained using a low shear screw configuration, were milled, all samples simply passed through the screen. When these milled granules were analyzed by sieve analysis, in all cases more than 98% of particles were less than 125 µm. Therefore, only when using a high shear screw configuration SC#1 and high temperature of 160 °C, could a lesser proportion of fines (<125 µm) be obtained in the case of HPMC HME 4M. The powder yield after milling in all cases was close to 100%, as there were no hard agglomerates present in this case, and thus no retention on the screen.
Granules obtained from melt granulation of metformin HCl with HPC GXF and HPMC HME 4M were milled using a co-mill. After milling samples were collected using screw configuration SC#1 in melt granulation, the ribbon-shaped extrudates were reduced to a powder. Particles obtained after milling of 100 and 120 °C granules showed a higher number of particles, less than <125 µm compared to 140 and 160 °C. This was due to the higher binding capacity of HPC GXF at a higher temperature. When melt-granulated samples, obtained with lower shear screw configuration SC#2, were milled, the particle size distribution remained comparable to that obtained with SC#1. Because these agglomerates are extremely hard and dense, some of these hard agglomerates remained in the mill and did not pass through the screen. The overall yield after milling was 85&#;90%.
Tablets were compacted using the milled granules at compaction forces of 15 and 30 kN. In the case of HPC GXF, tablets with acceptable hardness were obtained in all cases irrespective of the screw configuration or processing temperature. This showed that HPC GXF has a high binding capacity, even at low temperatures of 100 and 120 °C and with a minimum shear contributed from the screw configuration SC#2. HPMC HME 4M tablets obtained with extruded granules at 100, 120 and 140 °C were capped on compression. Only the HPMC HME 4M extrudate processed at 160 °C, with the high shear screw configuration SC#1 yielding coherent, strong tablets suitable for dissolution testing. No tablets were obtained with extrudates processed at any temperature with the low shear screw configuration SC#2. This indicated that HPMC HME 4M required a higher shear and temperature to fully melt and provide binding capacity. In contrast, HPC GXF-containing formulations were readily extrudable, yielding a consistent, molten extrudate over the entire processing temperature range of 100 to 160 °C. All the formulations that yielded tablets are shown in Table 4
3.6. Dissolution and SEM
Both HPMC HME 4M and HPC GXF have a similar molecular weight and viscosity; they are used for controlled-release tablet formulations. Tablets obtained from melt-granulated samples of metformin HCl with HPMC HME 4M and HPC GXF compressed at a compaction force of 15 kN were selected for dissolution studies.
w
/
w
for HPC GXF at one hour) as shown in
These tablets yielded similar dissolution profiles, regardless of the process temperature when compared at similar compaction forces. HPC GXF tablets compressed at 30 kN showed a further decrease in dissolution profiles which could be attributed to a decreased porosity. Dissolution profiles for tablets with melt-granulated samples of metformin HCl and HPMC HME 4M or HPC GXF were similar in the late time phase but HPMC HME 4M-based formulations had a higher burst effect compared to HPC GXF (69% in the case of HPMC HME 4M as compared to 44%for HPC GXF at one hour) as shown in Figure 3
Since the molecular weights of HPC GXF and HPMC HME 4M are comparable, both the polymers should provide similar swelling and drug release profiles. To investigate the burst release of the drug seen in the case of HPMC HME 4M, the SEM of the edge of the tablet was performed after one hour of the dissolution study. SEM micrographs showed the presence of large pores in the tablet in the case of HPMC HME 4M (shown in Figure 4 ), which explained the faster release of the drug through the matrix compared to HPC GXF. Tablets with HPC GXF showed very small pores in the matrix.
Rotational melt rheology: To provide efficient binding and granule properties, a polymer is required to regulate melt viscosity, so that it can deform and bind the particles together to provide granules. The rheological analysis of the polymer can guide a formulator on minimum processing temperature required for melt granulation process. The granulation capacity of the polymer may depend on its melt viscosity; therefore, a minimum processing temperature is required for a polymer to have an adequate low viscosity (or plasticity), so that it can deform itself and glue the drug particles to form the granules. In general practice, a parallel plate rheological study provides a basic idea on the selection of the minimum extrusion temperature required for the polymer. Glass transition temperature measured by differential scanning calorimeter (DSC) is not a sufficient indicator for guiding a formulator to choose the minimum extrusion temperature. The minimum extrusion temperature required by the polymer is often many degrees higher than its glass transition temperature measured by DSC.
6 Pa &#;s, to a glass-rubbery transition state, which is in between 104 and 105 Pa·s, eventually reaching its plastic state, which is below 104 Pa·s. In contrast, the continuous decrease in the complex viscosity from 106 to 104 Pa·s is monitored for HPC GXF because of its relatively lower glass transition temperature. Although it was reported that the complex viscosity should optimally be in the range of 103 to 104 Pa·s to enable melt extrusion, relying only on the complex viscosity is inadequate for selecting the right operational temperature for melt granulation, because it is not required that the polymer is fluid enough or has a low enough viscosity to dissolve the drug when flowing through the barrel and die in the extruder during melt granulation [
Because the extrusion process is more relevant to the polymer&#;s rheological properties, the minimum extrusion temperature could be indicated by the damping factor and tan δ value from a rheological temperature sweep. The minimum extrusion temperature is often higher than the polymer&#;s glass transition temperature, beyond which the tan δ starts increasing as a function of the temperature, indicating that the polymer chains overcome the intra- and inter-chain entanglements and start the plastic deformations. A temperature ramp from 90 °C to 200 °C is applied to investigate the effect of the temperature on the rheological behaviors of HPMC and HPC. The glass transition temperatures of HPMC HME 4M and HPC GXF are reported at 115 °C [ 31 ] and 84 °C [ 32 ], respectively; therefore, the temperature ramp tested is directly in the range of interest. The complex viscosity and tan δ as a function of the temperature are depicted in Figure 5 . As expected, both HPMC HME 4M and HPC GXF show decreases in the complex viscosity with the increase in the temperature. Specifically, the two stages&#; decrease in complex viscosity is observed for HPMC HME 4M because the low temperature end is below its glass transition temperature. The complex viscosity decreases from its glass state, which is above 10Pas, to a glass-rubbery transition state, which is in between 10and 10Pa·s, eventually reaching its plastic state, which is below 10Pa·s. In contrast, the continuous decrease in the complex viscosity from 10to 10Pa·s is monitored for HPC GXF because of its relatively lower glass transition temperature. Although it was reported that the complex viscosity should optimally be in the range of 10to 10Pa·s to enable melt extrusion, relying only on the complex viscosity is inadequate for selecting the right operational temperature for melt granulation, because it is not required that the polymer is fluid enough or has a low enough viscosity to dissolve the drug when flowing through the barrel and die in the extruder during melt granulation [ 17 ]. Moreover, the relatively close absolute values of the complex viscosity of both polymers make it very difficult to distinguish which is a better binder for the melt granulation process. However, tan δ seems to be a more reliable indicator for guiding the melt granulation temperature selection rather than the complex viscosity. In Figure 5 , tan δ signals successfully capture the glass transition of HPMC HME 4M, reflected by the peak around 119 °C. It is reported that the lower glass transition temperature is sufficient to significantly widen the processing temperature window of this HPMC HME 4M, but the tan δ also indicates that the minimum temperature needed to enable its plastic-dominant deformation is about 159 °C. On the contrary, the tan δ of HPC increases from 90 °C and reaches a semi plateau at 139 °C, indicating the melt granulation of HPC is possible when the temperature is above 90 °C. In summary, HPC should be a better melt granulation binder than HPMC HME 4M, with a broader processing temperature window, while HPMC HME 4M is only processable above 159 °C. The conclusion based on the rheological analysis is consistent with what was observed in melt granulation process.
η = η &#; + ( η 0 &#; η &#; ) × [ 1 + ( λ γ &#; ) α ] ( n &#; 1 ) α
(1)
η
0 and
η
&#; are the zero shear and infinite shear viscosity,
λ
is the relaxation time,
n
is power law index and
α
describes the transition region width. It was also reported that the infinite shear viscosity is very difficult to observe experimentally because the shear rate required for detecting it is very high and outside the normal measurement range. In this study, we could not capture the infinite shear viscosity for both samples. To obtain a more accurate curve fitting,
η
&#; was set to zero.
Aside from the processing temperature, the shearing force provided by the extruder contributes to the extrusion and deformation of the polymer. Therefore, a better understanding of the relationship between the shearing force and polymeric deformation is the key to guide robust screw design and the melt granulation process. Considerable efforts were devoted to establishing the structure&#;processing relationship via a rheological frequency sweep. Measurements of the complex viscosity at various frequencies at a single temperature can show if increasing the shear rate inside the extruder, either by increasing the screw speed or changing the screw configuration, is likely to improve the melt granulation. In this study, frequency sweeps within the linear viscoelastic region are conducted at low strains (<0.05) across an applied frequency range of 0.1 to 600 rad/s at different temperatures. Subsequently, the frequency sweeps are shifted into one master curve at the reference temperature of 140 °C by means of time-temperature superposition (TTS). Finally, the resulting complex viscosity profile from the master curve was fitted to the Carreau-Yasuda equation, which has a mathematic equation:whereandare the zero shear and infinite shear viscosity,is the relaxation time,is power law index anddescribes the transition region width. It was also reported that the infinite shear viscosity is very difficult to observe experimentally because the shear rate required for detecting it is very high and outside the normal measurement range. In this study, we could not capture the infinite shear viscosity for both samples. To obtain a more accurate curve fitting,was set to zero.
Figure 6 displays the complex viscosity&#;frequency data of HPMC HME 4M and HPC GXF in one master curve at the reference temperature of 140 °C. As shown in the figure, the TTS enables us to cover the rheological property of interest at 140 °C over a relatively broad frequency (time) range (~16 orders), which typically is not feasible when utilizing a single-frequency sweep because of the extremely long experimentation times and increased risk of sample degradation. Complex viscosity is one of the most important rheological properties that describes the processability of a material and can be directly correlated with molecular structure. In this study, both polymers show a typical shear-thinning behavior of polymeric melt, thus their complex viscosities display a strong dependence on the shear rate. Interestingly, both polymers show similar zero-shear viscosity due to their comparable molecular weights. Dependent on the substitution chemistry differences, however, the complex viscosity of HPC displays a stronger sensitivity to shear rate than HPMC does, manifested by a more pronounced shear thinning performance. In addition, other rheological properties, including relaxation time, the width of the transition region and power law index, have also changed correspondingly.
As a result, the master curves exhibited in Figure 6 are in good agreement with the modified Carreau-Yasuda model and the parameters fitting is conducted with sufficient accuracy. All obtained model parameters are summarized in Table 5 . In this manner, the rheological properties of HPMC HME 4M and HPC GXF, including the first Newtonian plateau, transition region, and shear thinning region, can be described, and compared quantitatively. Based on the fitting relaxation time, HPC shows one order less relaxation time than HPMC, indicating that it is more plastic and more easily deformed than HPMC under this temperature, making it a better melt granulation binder.
Hydroxypropyl cellulose (HPC) is a water-soluble polymer with many applications in food, pharmaceutical, medical, or paints industries. Past studies have reported that differences in functionality can occur between products of similar pharmaceutical grades. Understanding the origin of these differences is a major challenge for the industry. In this work, the structure and physico-chemical properties of several HPC samples of the same commercial grade were studied. Structural analysis by NMR and enzymatic hydrolysis were performed to study molar substitution and distribution of substituents along the polymer chain respectively. Water-polymer interactions, surface properties as well as rheological and thermal behavior were characterized to tentatively correlate them with the structure, and gain new insights into the structure-function relationship of this polymer. The differences in structure revealed between the samples affect their properties. The unexpected behavior of one sample was attributed to a more heterogeneous substitution pattern, with the coexistence of highly and weakly substituted regions along the same polymer chain. The more block-like distribution of substituents has a great effect on the clouding behavior and surface tension reduction ability of the polymer.
Hydroxypropyl cellulose (HPC) is a cellulose derivative in which some of the hydroxyl groups in the repeating glucose units have been hydroxypropylated. The resulting non-ionic polymer is soluble in water below its critical solution temperature and in many organic solvents [1]. The main features of HPC are its great surface properties [2] and its good film forming ability [3] compared to other cellulose ethers. Due to its unique properties, HPC has a wide range of industrial applications such as use in pharmaceutical tablets [4], ophthalmic inserts [5], smart windows [6], and as emulsifier/stabilizer in the food industry [7].
Like many other cellulose ethers, HPC is typically prepared by nucleophilic reaction of cellulose hydroxyl groups with electrophiles such as alkyl halides or epoxides [8]. The reaction is performed under heterogeneous conditions by a slurry process where cellulose is dissolved in aqueous sodium hydroxide, in the presence of an organic solvent [9]. Due to the flexibility of this manufacturing process, HPC can be obtained in several grades. The reaction rate as well as the number of substituents at positions 2, 3 and 6 is dependent on the alkali concentration [9]. Furthermore, the native cellulose materials greatly differ in structure depending on their origin [10], and the reaction with the electrophile tends to proceed faster in the amorphous regions than in the crystalline region [11]. As a result, cellulose ethers are thought to have an unbalanced distribution of substituents, with highly and poorly substituted regions existing on the same cellulose chain [12]. Commercial HPCs are typically characterized by average values of MW, hydroxypropoxy content (%), particle size, and viscosity, thus not accounting for the variability that may exist within the sample.
Some authors have already reported that differences in properties can occur between products formulated with hydroxypropylmethyl cellulose (HPMC) of similar pharmaceutical grades [13]. It was reported that HPMC with the same substitution and viscosity grade can have significantly different cloud points (CP) [14] or polymer release from matrix tablet [15,16]. HPC has received much less attention in the literature, but a study of Desai et al. suggests that such differences may also exist between HPCs of the same grade [17]. They studied the effect of HPC on the dissolution of pharmaceutical tablets and reported differences in performance between HPCs from different suppliers that both met the National Formulary criteria. These differences in properties between materials of same grade represent a challenge for the industry, and the current knowledge on this subject still contains many grey areas.
The distribution of substituents within the anhydroglucose unit and molecular chain is known to be an important parameter determining the physico-chemical behavior of cellulose derivatives in general [18]. The chain architecture affects the inter- and intramolecular hydrogen bonding formation, which impact a series of parameters such as solubility, crystallization, chemical reactions of hydroxyl groups [19] and gelation [20]. The knowledge about the impact of structure on the functionality of HPC has been increasing over the years. The influence of the molar substitution (MS) and MW is fairly well established. The relationships between MS and (i) the interaction with water and the equilibrium moisture content [21,22], (ii) the glass transition temperature [23], and (iii) the CP [22] were established a long time ago. The MW of the polymer is known to be positively correlated with the viscosity of aqueous solutions, and that shorter chain polymers (lower MW) show less shear thinning [7]. The impact of MW on surface tension (SFT) was also investigated [24]. The authors reported that MW has a significant effect on the adsorption kinetics at the interface; lower MW molecules decreased the SFT faster, which was attributed to their higher diffusion coefficient. On the other hand, the MW had little influence on the SFT at equilibrium. A link between the CP and the distribution of substituents along the polymer chain has been suggested by Schagerlöf et al. () [25]. However, the consequences of differences in distribution of substituents along the polymer chain and the impact on important functional properties such as surface-activity, and rheological behavior has often been overlooked. Most studies investigating the link between structure and function have focused on HPC-water interactions [21,26,27] or dissolution from tablet [17,28]. Since the functionality of these polymers is largely dictated by their structure, a more detailed study of the structure-properties relationship is required. Accordingly, the aim of this paper was to identify the origin of these differences, as well as to provide a better understanding of the structure-function relationship of this polymer.
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