The number of poorly soluble drugs continues to increase. Forty percent of drugs currently on the market exhibit poor solubility, and 90% of active ingredients in development are poorly soluble (1). The interest in finding methods to increase solubility and dissolution rate is therefore growing. Industry uses various approaches to achieve these goals, many of which can be found in the literature.  

Some methods manipulate the structure of the drug (e.g., they incorporate certain groups to generate a prodrug or the creation of different salts with higher solubility) (2). Other methods are physical such as decreasing the drug's particle size (e.g., micronization or nanosizing, crystal habit modification, complexation with cyclodextrins, generation of polymorphic forms or solubilization) (3). The most widely used approach is to form solid dispersions of the drug in a carrier, where the drug is present as amorphous or crystalline regions in a carrier, or—more preferable with respect to stability—the drug is dissolved molecularly in the polymer. In either case, solubility can be enhanced because there is no lattice energy to overcome to dissolve the drug. After the carier is dissolved, the drug is released to media already in a dissolved state. Besides other polymers, polymethacrylates such as Eudragit (Evonik Röhm GmbH, Darmstadt, Germany) are amorphous and more ideal for preparing solid dispersions.   

Solid dispersions can be prepared using various techniques. Among these, spray-drying and melt extrusion have proved to enhance solubility. Both techniques have advantages as well as limitations. In the case of a drug with a high melting point, spray-drying is the method of choice because the temperature applied in the melt extruder is limited by the carriers' thermostability. Another limitation to melt extrusion is its application for temperature-sensitive drugs. In these cases, spray-drying could be better applied. One limitation to spray-drying is that, in some cases, there is no solvent available to dissolve the polymer and the drug. In this situation, melt extrusion has an obvious advantage. Organic solvents can lead to problems such as residual solvents in the product, lack of security during production, and environmental issues.  

A previous article described the increase in dissolution from melt extrudates containing Eudragit E, Eudragit NE 30D, and felodipine (4). Eudragit NE 30D is a water-insoluble polymer conventionally used for sustained-release applications in coatings, matrix systems, and melt extrusion. In small portions, Eudragit NE 30D can be used as stabilizing agent. It swells and is dispersed as fine particles in the media, seperating the drug particles from each other and hindering precipitation.  

This article compares these results with a similar formulation, prepared by spray-drying. The authors discuss how melt extrusion and spray-drying can be used to prepare solid dispersions of poorly soluble drugs with Eudragit polymers. These solid dispersions show comparable results in dissolution rate, X-ray powder diffraction (XRPD), and differential scanning calorimetry (DSC).   

 Felodipine for spray-drying was purchased at Shiono Chemical Co. (Tokyo) for melt-extrusion trials in Zhejiang Yiyuan, China. Carbamazepine was a gift from Evonik (Dossenheim, Germany). The authors also used Eudragit E and Eudragit NE30D (Evonik Röhm GmbH, Darmstadt, Germany) and ethanol (Wako Pure Chemical Industries, Osaka, Japan).  

Eight-five percent of 5% Eudragit E PO, 5% Eudragit 30D, and 10% felodipine were dissolved in ethanol (95%). The organic solution contained 14% of solid. Ten percent carbamazepine and 90% Eudragit E PO were dissolved in ethanol (95%) with a solid content of 6%. The spray-drying process was conducted with a Mini Spray-Dryer B-290 (Buech, Tokyo). Operational conditions are described in Table I. 

 XRPD was carried out on a Mini-Flex, DSC was carried out on a Thermo plus 2–DSC 8230 (Rigaku, Tokyo), and the scanning electronic microscope (SEM) used was a JSM–6360LV (Jeol, Tokyo). 

Solubility was measured with high-performance liquid chromatography (HPLC). The drug, the physical mixture, or the spray-dried sample was dispersed in 0.1N hydrochlorid acid (pH 1.2); the dispersion was homogenized with ultra sonic vibration for 10 min and filtered. Solutions with felodipine were diluted with the mobile phase acetonitrile/0.01 M phosphate buffer pH 4.5 (70/30). The wavelength was set to 237 nm and the flow rate was 1 mL/min. Dissolution testing was performed with a paddle apparatus (DT610, Jasco, Tokyo), at a rotation speed of 100 rpm. The authors used 900 mL of 0.1N hydrochlorid acid (pH 1.2) and added samples equivalent to 18 mg of felodipine or 360 mg of carbamazepine. The wavelength was set to 237 nm for felodipine and 285 nm for carbamazepine.  

 Solid dispersions containing felodipine (melting point=145 °C), Eudragit E, and Eudragit NE 30D (10%/85%/5%) and solid dispersion with 10% carbamazepine (190 °C) and 90% Eudragit EPO were prepared by melt extrusion on a twin-screw extruder (Micro 18 GL Pharma, Leistritz, Nürnberg, Germany). The temperature profile of the felodipine sample was between 70°C and 160°C, the screw speed was set at 200rpm, the feeding rate of the solids at 0.7 kg/h and Eudragit NE 30D was dosed with a hose pump. For the carbamazepine sample, the temperature was between 70 °C and 200 °C, the screw speed was 150 rpm, and the feeding rate of the solids was set at 0.5 kg/h. The extrudate was pushed through an orifice, collected on a conveying belt, and granulated. The granules were milled to 250 µm.  

XRPD was carried out on an X'Pert Pro MPD Diffraktometer (Panalytical, Almelo, The Netherlands),  DSC was done with a Pyris 1 DSC (Perkin Elmer, Waltham, MA). Dissolution testing was performed with a paddle apparatus (DT 700, Erweka, Heusenstamm, Germany) at a rotation speed of 100 rpm. The authors used 500 mL of simulated gastric fluid sine pepsin (SGFsp) at a 1.2 pH and added samples equivalent to 10 mg of felodipine or 200 mg of carbamazepine. The concentration of felodipine was measured with HPLC using acetonitile/phosphate buffer pH 3/methanol 40/40/20 % (v/v/v) as a mobile phase. The wavelength was set to 362 nm and the flow rate was 1 mL/min. The concentration of carbamazepine was measured with an ultraviolet spectrometer at a wavelength of 285 nm.  

Physical mixtures were prepared by blending the substances for 10 min at 40 rpm in a double-cone mixer (Erweka, Heusenstamm, Germany). For the physical mixture containing Eudragit NE 30D, the dispersions were dried to obtain a solid. 

For the spray-dried samples, the residual solvent content was measured by loss on drying with infrared (IR) spectroscopy. Less than 0.95 wt% of residual ethanol content in the spray-dried sample was found and presumed not to influence XRPD, DSC, or stability.   

Spray-drying and melt extrusion with felodipine. 

In a previous study, 10% of felodipine was identified as the optimum drug load with respect to dissolution (3). Spray-dried samples, therefore, were produced with a 10% drug load and compared with the results of an extrudate with the same formulation used in a previous study (3). Spray-dried and extruded samples were analyzed with DSC and XRPD to evaluate the crystallinity of felodipine in the samples. In XRPD (see Figure 1), no typical peaks referring to felodipine could be observed in the spray-dried sample or in the extrudates. In comparison, the corresponding physical mixture showed peaks in XRPD at 10.23 (2θ), 10.88(2θ), 16.6(2θ), 20.5 (2θ) und 23.7(2θ), where θ is defined as the incident angle of the X-ray (i.e., the angle between the incident X-ray and the plane of the sample). Because Eudragit polymers are amorphous and the positions of the peaks are equal to pure felodipine, these peaks are clearly related to pure felodipine. Both methods lead to a formation of a solid dispersion of felodipine, Eudragit E and Eudragit NE 30 D.    

Figure 1 (All figures are courtesy of the authors.) 

These results were confirmed with DSC. The DSC runs of pure felodipine, a physical mixture, and the spray-dried and extruded samples can be seen in Figure 2. In the physical mixture and in the pure felodipine, a melting peak was detected, whereas in the spray-dried sample and in the extruded sample, no melting peak was observed. Only one glass transition temperature (

 value in the melt-extruded sample is below the 

 value of the pure polymer, meaning felodipine has a slightly plasticizing effect on the polymer. The appearance of a single Tg is an indication for the formation of a glassy solution where the drug is dissolved in the polymer. 

The formation of a solid glassy solution leads increases the dissolution rate and apparent solubility of felodipine. In Figure 3, the solubility of the spray-dried sample is compared with the solubility of pure felodipine and the physical mixture. For felodipine, no solubility was detected because the value was below the detection limit. The physical mixture increased in solubility (40 µg/mL), because of to the wetting properties of Eudragit. The spray-dried sample increased the solubility of felodipine 8.5-fold to 340 µg/mL. This tremendous increase in solubility is caused by the formation of a solid dispersion. In Figure 4, the SEM picture of pure felodipine and the spray-dried powder can be seen. Pure felodipine appears as cubic crystals; in the spray-dried powder, no felodipine crystals are observed. 

In Figure 5, the dissolution profiles of the extrudate and the spray-dried powder are compared with those of pure felodipine in acidic media. Dissolution of extrudates was described in a previous study (4) and is used for comparison with the spray-dried sample. Crystalline felodipine, as expected, shows nearly no dissolution because its solubility in 0.1N hydrochlorid acid (pH 1.2) is very poor (1 mg/mL). 

The spray-dried sample shows a clear increase in dissolution rate comparable with the extrudate. The combination of the two polymers in spray-drying and in melt extrusion generates a product with a high initial release, based on Eudragit E and a stabilization of the profile with Eudragit NE 30 D. Eudragit E is known to increase the dissolution rate of poorly soluble drugs (5). 

The average difference for all time points between dissolution curves of the spray-dried sample and the extrudate was less than 10%, meaning the dissolution profiles were similar. Although the dissolution tests were performed under different conditions and only three units per test were used, the similarity factor (

				 value of ~70, which proves the similarity of the dissolution curves. 

Spray-drying and melt extrusion with carbamazepine.

 Spray-dried and melt-extruded samples containing Eudragit NE 30D E and carbamazepine were analyzed with XRPD and dissolution testing. Neither samples exhibited crystalline peaks in XRPD analysis (see Figure 6), thereby showing that an amorphous state of carbamazepine is likely. For the pure carbamazepine, crystalline peaks were observed corresponding to the polymorphic modification stable at room temperature. The physical mixture also showed crystalline peaks at 13.14(2θ), 15.36(2θ), 15.94(2θ), 17.18(2θ), 19.6(2θ), 25.02(2θ), and 27.42(2θ), corresponding to carbamazepine crystal of modification 3. 

In Figure 7, the dissolution profile of the spray-dried sample and the extrudate are compared with the physical mixture. For both solid dispersions, a 100% release was observed. Eudragit E dissolved rapidly in the acidic media and exposed carbamazepine already in a dissolved state. The spray-dried sample demonstrated a complete release within the first 5 min, whereas the release from the melt-extruded samples was slightly slower, reaching a complete release after 20 min. During dissolution, the powder in the melt-extruded samples agglomerated at the beginning, slightly retarding the release of the drug. In addition, the particle sizes of the milled extrudate were larger than those of the spray-dried sample. 

Stability results for melt-extruded samples are available and showed a stable profile over a storage period of 6 months at elevated conditions (see Figure 8). The same results can be expected of the spray- dried samples if the same polymer is used. Stability of spray-dried samples is currently under investigation. Overall, Eudragit E is a suitable carrier for increasing the dissolution of carbamazepine and stabilizing a drug during storage. 

Two model drugs were seleceted and formulated with Eudragit using spray-drying and melt extrusion techniques. XRPD and DSC were used to characterize the obtained solid dispersion. Spray-dried and extruded samples showed a high increase in solubility for both drugs. The profiles were comparable, meaning that both techniques can be used to increase the drug's dissolution rate. Each method has advantages. In the case of a high melting drug, spray-drying is the method of choice. On the other hand, because melt extrusion is a solvent-free process, no drying is required and one can avoid the problem of having to find a suitable solvent. The melt-extrusion technique seems not to be crucial for preparing a solid dispersion. A more important prerequisite is the miscibility of polymer and drug. Both poorly soluble drugs were miscible with Eudragit, demonstrated by the appearance of only one 

 in DSC. Non-miscible systems are likely to recrystallize and show stability problems. Miscible systems form a more stable solid dispersion as the drug is dissolved in the polymer.   

Eudragit polymers are well known and widely used in coating and matrix applications. This study showed that Eudragit polymers are also suitable to succesfully increase the solubility of poorly soluble drugs 

 by forming stable solid dispersions with the drug.  because of to the increase in solubility, an increase in bioavailability 

 will occur. Furthermore, the study shows that both melt extrusion and spray-drying can be used to obtain solid dispersions with Eudragit polymers and drugs leading to comparable results. 

 is the technical manager of melt extrusion and 

 is the technical marketing manager of technology commercialization, both at Evonik Röhm GmbH, Kirschenallee, 64293 Darmstadt, Germany, tel. +49 6151 18 4292, fax +49 6151 18 3249, 

 is a research scientist on technical service, both at Evonik Degussa Japan Co. 

*To whom all correspondence should be addressed. 

 1.  L. Benet et al., "Predicting Drug Absorption and the Effects of Food on Oral Bioavailability," 

 2.  G.L. Engel et al., "Salt Form Selection and Characterization of LY333531 Mesylate Monohydrate," 

 3.  C. Leuner and J.Dressman, "Improving Drug Solubility for Oral Delivery Using Solid Dispersions," 

 4.  K. Nollenberger and S.  Brühne S., "Pair Distribution Function X-ray Analysis Explains Dissolution Characteristics of Felodipine Melt Extrusion Products," 

 5.  Biovail Technologies Ltd., "System for Rendering Substantially Non-Dossoluble Bio-Affecting Agents Bio-Available," US patent US 6391338± (May 21, 2002). 

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The authors demonstrate how melt-extrusion and spray-drying methods can help to prepare solid dispersions of poorly soluble drugs using Eudragit polymers.

Using Polymers to Enhance Solubility of Poorly Soluble Drugs

Dissolution is essential for a drug to be absorbed through the biological membranes into systemic circulation for therapeutic efficacy. Conventional tablet formulations generally require rapid disintegration to aid drug dissolution. Superdisintegrants are added to oral solid dosage formulations to facilitate disintegration. Commonly used superdisintegrants such as crospovidone, croscarmellose sodium, and sodium starch glycolate are highly efficient at low concentration levels (2–5 w/w%) in the tablet formulation at facilitating the rate and extent of tablet disintegration. The correlation between tablet disintegration and drug dissolution, however, is not always observable (1–3). 

One recent study, for example, evaluated the respective effects of crospovidone, croscarmellose sodium, and sodium starch glycolate on the dissolution behavior of eight cationic drugs from a model direct-compression tablet formulation with 2% w/w superdisintegrant (4). No significant differences were observed in the disintegration times of the tablets. However, the study did show that crospovidone demonstrated a more rapid dissolution rate than the other superdisintegrants for the cationic drugs studied, irrespective of the drug's aqueous solubility.   

The dissolution studies were performed for each drug in the compendial media for the drug. Crospovidone provided the fastest dissolution in the compendial media for seven of the eight drugs. Because crospovidone is nonionic, ionic interaction between this superdisintegrant and the cationic drug was impossible. In contrast, croscarmellose sodium and sodium starch glycolate are both anionic, and these superdisintegrants could potentially interact with cationic drug actives and slow their dissolution. As a result of these observations, the authors recommended formulation screening of superdisintegrants during excipient selection to minimize dissolution retardation resulting from any drug–excipient interaction. 

More than 60% of new drugs currently in development today are considered poorly soluble, as are nearly half of the drugs whose patents will expire in the next 10 years. Selecting formulation ingredients that enhance the dissolution of poorly soluble drugs has therefore become increasingly important to achieve therapeutic efficacy. Once a tablet disintegrates, the solubility properties of the drug, either alone or assisted by other formulation ingredients, determine the drug's subsequent dissolution rate and extent of release. Water-soluble drugs provide rapid and high-level drug release. However, other ingredients in the formulation of poorly soluble drugs, including the disintegrant, must play a key role in determining the finished formulation's drug-dissolution characteristics. With that in mind, this study was conducted to explore the impact of superdisintegrant selection on the rate of dissolution of poorly soluble drugs. 

 Table I lists the 13 poorly soluble active ingredients tested. Their aqueous solubilities were 2–2300 µg/mL. The superdisintegrants studied were crospovidone Type A (Polyplasdone XL, International Specialty Products, ISP, Wayne, NJ), crospovidone Type B (Polyplasdone XL-10, ISP), croscarmellose sodium (Ac-Di-Sol, FMC Biopolymer, Philadelphia, PA), and sodium starch glycolate (Glycolys, Roquette, Tokyo). As outlined in the 

 crospovidone is available in different particle sizes. Crospovidone Type B has a smaller average particle size than crospovidone Type A. 

 Tablets were prepared at the highest market dose using a direct compression (DC) or wet granulation (WG) process as considered appropriate through a review of the ingredients listed in the 

For tablets prepared by direct compression, required ingredient quantities were weighed and blended to form a homogeneous powder mix. The blends were then compressed using appropriate tooling on a 16-station, instrumented, rotary compression machine (CMD4, Cadmach, Ahmdedabad, Gujarat, India). Advanced Instrumentation Monitor (AIM) software, (Metropolitan Computing Corporation, East Hanover, NJ) was used with the tablet press to determine the compression force required to yield tablets of approximately equal hardness for the various drugs used in the study. Formulations used to prepare atorvastatin and loratadine tablets by direct compression are shown as examples in Tables II and III, respectively. 

For tablets prepared by wet granulation, weighed amounts of drug, diluent, and binder were premixed for 60 s in a granulator bowl (4M8, Pro-C-Ept, Zelzate, Belgium) at an impeller speed ranging from 1000 to 1200 rpm. Water was added at a predetermined rate, and after 120 s, the chopper was started (2300–2500 rpm). Granulation proceeded for 10 min. The impeller torque and the product temperature were monitored to determine the end point of granulation. The granules were sieved through specified mesh and dried in an oven at 60 °C, to a final moisture content of 1.5–2% w/w, measured using a moisture balance (MA45, Sartorius, Goettingen, Germany). The required quantities of remaining ingredients were weighed and blended with the granules to form a homogeneous powder mix. The blends were then compressed as previously described. Formulations used to prepare efavirenz and ezetimibe tablets by wet granulation are shown as examples in Tables IV and V, respectively. 

 The respective breaking forces of the prepared tablets were determined 24 h after compression using a hardness tester (TBH 310 MD, ERWEKA, Heusenstamm, Germany). Ten tablets from each batch prepared were tested for tablet breaking force, and the mean and standard deviation were calculated. 

. Respective disintegration times of the prepared tablets were measured in 900 mL of purified water with disks at 37 °C using a TAR series tester (ERWEKA). Disintegration times of six individual tablets were recorded. 

Figure 1 (All figures are courtesy of the authors) 

 The dissolution studies of the prepared tablets were carried out using US Pharmacopeia (USP) Apparatus 2 (Vankel VK, Palo Alto, CA). Dissolution profiling was performed with the medium recommended by USP or the US Food and Drug Administration for the respective drug. Dissolution profiling was also carried out in a medium developed in house and derived from the recommended media, capable of discriminating between the formulations. A peristaltic pump was coupled to a UV–visible spectrophotometer (Carry 50, Palo Alto, CA) to provide a continuous flow of the drug solution through a 1-cm cuvette. Samples were programmed to be analyzed at 5, 10, 15, 30, 45, and 60 min at the λ max of the respective drugs. The time required to achieve 80% drug release (

) was considered for comparing dissolution results. The 

 was determined by fitting the dissolution data to a four-parametric logistic model using the Marquardt–Levenberg algorithm (Sigmaplot 9.0, SPSS, Chicago). 

 represents the cumulative percent of drug released, 

 is the time in minutes, "min" is the baseline of percent drug released at 0 min, "max" is the plateau of percent drug released at 60 min, and "hillslope" is the slope of the curve at transition center EC

Although crospovidone, croscarmellose sodium, and sodium starch glycolate are used to provide the same function within the formulation, they differ in their chemical structure, particle morphology, and powder properties. 

Croscarmellose sodium is the sodium salt of a cross-linked, partly 

-(carboxymethylated) cellulose, and sodium starch glycolate is the sodium salt of a carboxymethyl ether of starch or of a cross-linked carboxymethyl ether of starch (5). Both materials are sodium salts and are anionic. In addition, their polymer backbones are composed mostly of glucose repeat units. In contrast, crospovidone is an insoluble, cross-linked homopolymer of 

-vinyl-2-pyrrolidone and is nonionic. Chemically, the repeat structure of crospovidone is similar to that of 

-methylpyrrolidone, a water-miscible, polar aprotic solvent with high interfacial activity used as a solubilizer in many applications. 

When examined under a scanning electron microscope, croscarmellose sodium particles have a fibrous, nonporous structure; sodium starch glycolate particles are spherical and nonporous; and crospovidone particles (Type A and Type B) appear highly porous and granular (see Figures 1–4). Both crospovidone types have similar particle morphology, but differ in particle size. Table VI shows a comparison of the superdisintegrants' typical average particle size and surface area (Mastersizer, Malvern, Worcestershire, England) and Brunauer, Emmett, and Teller gas adsorption, respectively. Crospovidone Type B had the smallest particle size and the highest surface area. The high surface area increases interfacial activity that can aid in drug dissolution. Thus, the unique chemical structure and powder properties of crospovidone Type B may improve the dissolution of poorly soluble drugs. 

Drug-dissolution profiles are increasingly used to evaluate drug-release characteristics of pharmaceutical products. The dissolution media adopted by the pharmacopeias or recommended by FDA for 

dissolution testing are designed to maximize drug release. Thus, the recommended medium for a given marketed drug becomes the quality-control standard to ensure that batch-to-batch consistency and continuing product quality and performance are maintained regardless of changes in the manufacturing process. Although the recommended media for 

dissolution testing can guide formulation development, it typically does not discriminate between formulation ingredients because a poorly soluble drug's release is usually affected more by the medium than the formulation ingredients. 

Discriminatory dissolution profiles are highly desirable for distinguishing between products with different pharmaceutical attributes (e.g., formulation or manufacturing-process differences) (6). In the present study, dissolution testing was conducted in the recommended media for the drug as well as in modified dissolution media that were designed to produce drug-release profiles that discriminate between formulations with different superdisintegrants. The formulations for a given drug were produced using the same process, ingredients, and ingredient levels. In addition, tablets were compressed to equivalent hardness to minimize the effect of the tablet's physical properties on the dissolution results. Only the selection of superdisintegrant varied. The discriminating media were selected so that at least one formulation achieved 80% drug release. Table VII shows the recommended and discriminating media for each drug tested. 

For the 13 poorly soluble drugs evaluated, no significant differences were observed in the breaking force and disintegration times of the tablets prepared using the various superdisintegrants for a given drug studied (see Table VIII). 

Figures 5–12 show the dissolution profiles for the tablets with atorvastatin, loratadine, efavirenz, and ezetimibe in the recommended and discriminating media as examples. The dissolution profiles indicate that the tablets with crospovidone Type B, in both the recommended and discriminating media, had the fastest rate of dissolution. Thus, even though the superdisintegrants gave similar disintegration results, the choice of superdisintegrant had a significant effect on drug dissolution. Because the discriminating media showed even greater differences in dissolution rate between the superdisintegrants studied, the discriminating media were highly effective at identifying differences between the superdisintegrants selected. 

 results for all 13 drugs studied in both media. In the recommended media, crospovidone provided the fastest 

 for 12 of the 13 drugs studied. Crospovidone Type B provided the fastest 

 for 10 of the 13 drugs studied. In the discriminating media, crospovidone Type B provided the fastest release for all drugs. A discriminating medium for raloxifene HCl tablets was not developed because the recommended medium was sufficiently discriminating. Therefore only 12 drugs were evaluated in a discriminatory medium. Furthermore, crospovidone Type B was often the only superdisintegrant to yield a formulation of the most poorly soluble drugs that achieved 80% drug release in the discriminating media. Overall, the results suggest that crospovidone Type B is more effective than the other superdisintegrants in enhancing the dissolution rate of poorly soluble drugs. Crospovidone Type B has solventlike chemistry and high surface area, resulting in high interfacial activity that enhances drug dissolution and release. 

At a time when formulators are faced with increasing numbers of poorly soluble drugs, it has become very important to select superdisintegrants to maximize drug dissolution. A comprehensive study conducted to evaluate the effect of crospovidone, croscarmellose sodium, and sodium starch glycolate on the dissolution rates of poorly soluble drugs with varying aqueous solubility showed crospovidone Type B to provide the fastest rate of dissolution for poorly soluble drugs. The fact that tablet strength and disintegration times for the tablets containing each drug and all the superdisintegrant studies were similar showed that tablet hardness and disintegration did not influence dissolution. Crospovidone Type B has unique chemistry, particle size, and particle morphology that result in high interfacial activity, which significantly aids dissolution. 

The authors wish to acknowledge the support and contributions of ISP's pharmaceutical research and development and analytical scientists in Hyderabad, India, and Wayne, New Jersey. 

 is a manager of pharmaceutical research and development at International Specialty Products India, and 

 is a senior director of pharmaceuticals at International Specialty Products, 1361 Alps Rd., Wayne, NJ 07470, tel. 973.628.4148, 

The authors examine common superdisintegrants (i.e., crospovidone Type A, crospovidone Type B, croscarmellose sodium, and sodium starch glycolate) with a set of poorly soluble drug actives and evaluate in vitro drug dissolution.

Influence of Superdisintegrants on the Rate of Drug Dissolution from Oral Solid Dosage Forms

Hydrophilic gel-forming matrix systems are widely used in oral controlled-release dosage forms. Hydrophilic polymer hydrates form a viscous gel layer around the tablet surface, and drug release is controlled in a sustained manner by diffusion through a gel layer and the erosion of the gel (1). Drug solubility, however, greatly affects the rate of diffusion and erosion. It is especially difficult to control the release rate of highly water-soluble and insoluble drugs (2–4). Moreover, various gastrointestinal factors such as ionic strength and mechanical destructive force also affect the drug-release rate (5–8). To solve these problems or predict these influences, many studies have examined factors affecting drug release.  

In this study, a highly functional pregelatinized starch (HS) was investigated as the potential basis for developing a hydrophilic matrix system for sustained release (9). The influence of drug solubility and external factors such as ionic strength, mechanical force, and accelerated storage conditions on the drug-release rate was evaluated. In addition, the effect of polyethylene glycol (PEG) on drug-release profiles was investigated to obtain zero-order release profiles. 

 Figure 1 (All figures are courtesy of the authors.) 

HS was prepared by controlled thermal pregelatinization of potato starch and a spray-drying technique. It is compatible with the 

National Formulary, European Pharmacopoeia, 

The properties of HS are shown in Table I. HS has different properties from conventional pregelatinized starches and conventional hydrophilic gel-matrix excipients because of its high viscosity and insoluble element in dissolution media (see Figure 1).  

 Ethenzamide (ETZ), acetaminophen (APAP), and sodium salicylic acid (SSA) were used as model drugs and may be characterized as water-insoluble, moderately water-soluble, and highly water-soluble drugs, respectively. All drugs were purchased from Yoshitomi Pharmaceutical (Tokyo).  

HS was prepared by Asahi Kasei Chemicals (Tokyo). Hydroxypropyl methylcellulose [(HPMC) Metolose 90SH-100SR, Metolose 90SH-4000SR, Metolose 10000SR] was purchased from Shin-Etsu Chemical (Tokyo).  

 Partially pregelatinized corn starch (Starch 1500) was purchased from Colorcon (West Point, PA). Fully pregelatinized corn starch (Amycol C) and fully pregelatinized potato starch (Amycol HF) were purchased from Nippon Starch Chemical (Osaka, Japan). Microcrystalline cellulose (MCC), Ceolus KG-802, was manufactured by Asahi Kasei Chemicals. PEG (Macrogol 6000) was supplied by Sanyo Chemical (Kyoto, Japan). Sorbitol (Sorbitol SP) was purchased from Kowa Pharmaceutical (Nagoya, Japan). 

Evaluation of properties of modified starches and HPMC. 

Measurement samples of 5 g were sieved for 5 min using an air-jet JIS sieve of 20, 38, 75, and 150 µm-mesh. The weight percent remaining on each sieve after sieving was calculated, and the particle diameter was calculated as the cumulative weight percent of 50%. 

Sample dispersions of 1% were prepared at 20 °C and were centrifuged for 15 min at 5000 G. The supernatant was dried at 105 °C until a constant weight was reached. The dry weight was defined as the amount of soluble content and was expressed as a percentage of the initial weight of  the samples. 

The viscosity of 2% sample dispersions was determined at 25 °C with a rotary viscometer (TVB-10, Toki Sangyo, Tokyo) using an M1 body. 

A model drug, a matrix excipient, and other excipients were physically admixed. The mixtures of 180 mg were compressed using an 8.0-mm diameter round-faced punch at compression pressure of 60 MPa. 

The dissolution tests were carried out at 37 °C ± 0.5 °C using a USP Type 1 apparatus or a USP Type 2 apparatus rotating from 50 to 200 rpm. The test media consisted of 900 mL of second fluid of the

 (14th edition) (JP-2, pH 6.8, and ionic strength 0.14 M) and McIlvaine buffer (pH 7.2 and ionic strength 0.39 M).  

Stability test under accelerated conditions.

 Dissolution profiles and the yellowness index (YI) of HS and HPMC matrix tablets were evaluated after storage at 40 °C and 75% relative humidity (RH) in sealed glass bottles, and at 60 °C in polyamine–polyethylene bags. The YI was measured by a spectrophotometer (SE200, Nippon Denshoku, Tokyo). 

Preliminary screening of matrix excipients: influence of α-amylase in dissolution media. 

Several thermally modified starches were investigated as matrix-forming excipients for sustained-release tablets (10–14). These studies pointed out that only fully pregelatinized starches functioned for the purpose of forming matrices because of their high gelling capacities (11, 13, 14). However, it was reported that matrix tablets with fully pregelatinized starch could not provide stable drug-release profiles when α-amylase was added in test media to mimic the gastrointestinal environment (11).  

The influence of α-amylase on drug release from HS matrix tablets was investigated and  compared with commercially available partially and fully pregelatinized starches. Four different tablets, composed of APAP, MCC, and modified starch (HS, Starch 1500, Amycol C, and Amycol HF) were tested.  

Figure 2 shows the dissolution profiles of APAP from various starch matrix tablets (starch/APAP/MCC = 60%/10%/30%) in different two buffers, JP-2 buffer without α-amylase (see Figure 2a) and JP-2 buffer with α-amylase in a 5-g/L concentration (see Figure 2b). The activity of α-amylase was adjusted to 1700 IU/L, which is close to the median α-amylase activity in pancreatic juice (11).  

Matrix tablets made of conventional partially pregelatinized corn starch disintegrated completely within 0.5 h, and sudden APAP release occurred. For both fully pregelatinized starches, sustained- release profiles were obtained in media without α-amylase. However, the drug-release rate from the fully pregelatinized starch matrix changed faster in media containing α-amylase. These results were the same phenomenon as described in previous work (11). On the other hand, matrix tablets made of HS were well controlled in the same way, with or without α-amylase. This situation can be explained by the high gel-forming ability of HS with high viscosity to prevent the dissolution and by the high resistance to α-amylase based on its degree of pregelatinization. HS has the same viscosity as HPMC and the moderate degree of pregelatinization between conventional partially pregelatinized starches and fully gelatinized starches (see Table I) contributes to its good balance of resistance to α-amylase and the gel-forming ability.  

Based on this prescreening test, the following evaluations were done with HS and HPMC as matrix excipients: a dissolution study under high ionic-strength conditions, a dissolution study under high mechanical-force conditions, a zero-order release, and a storage stability of dissolution profiles and of tablet color. 

Dissolution study under high ionic-strength conditions.

 The influence of ionic strength of dissolution media on APAP release rate was investigated. HS or HPMC matrix tablets containing APAP and MCC were prepared (HS or HPMC/APAP/MCC = 60%/ 10%/30%) and tested for dissolution using two media of different ionic strength: JP-2 buffer (ionic strength 0.20 M) and McIlvaine buffer (ionic strength 0.39 M). 

Figure 3 shows the release profiles of APAP from HS and HPMC matrix tables. The release profiles of APAP from HS matrix tablets hardly changed between the JP-2 buffer and the McIlvaine buffer, but the profiles of HPMC were largely influenced by ionic strength. The HPMC matrix tablet couldn't maintain its matrix structure at high ionic-strength conditions, and burst release of APAP occurred. These results were caused by the difference in swelling ability in high-ionic-strength conditions. In the case of HPMC, as the ionic strength increases, the degree of swelling attributable to hydration decreases because the amount of water available to hydrate HPMC was reduced when more water is required to keep the ions in solution (5). In contrast, HS has a lot of hydroxyl groups on its backbone, so HS could hydrate in high ionic-strength conditions without competing with electrolytes. 

Dissolution study under high  mechanical-force conditions

. The influence of mechanical force at different rotation speeds on the APAP release rate was investigated. Figure 4 shows dissolution profiles of APAP from HS or HPMC matrix tablets (HS or HPMC/APAP /MCC = 60%/10%/30%). The experiments were performed using a USP Type 1 apparatus at a rotation speed of 100 rpm in a JP-2 buffer containing α-amylase in a 5-µg/L concentration. Under these conditions, the release rates of APAP from the HS tablet and the HPMC tablet were almost identical, but the drug-release mechanisms were different. HS matrix tablets were hardly eroded, whereas HPMC matrix tablets gradually became smaller by erosion. 

Figure 5 shows the dissolution profiles of APAP of HS or HPMC matrix tablets (HS or HPMC/APAP/MCC = 60%/10%/30%). The experiments were performed using a USP Type 2 apparatus at rotation speeds of 50 or 200 rpm in a JP-2 buffer containing α-amylase in a 5-µg/L concentration. Under these conditions, the drug-release profiles of HPMC were remarkably accelerated by increasing rotation speed. On the other hand, those of HS matrix tablets were hardly affected by rotation speed. The difference of 85% APAP release time between 50 and 200 rpm of HPMC and HS were respectively 3.4 h and 0.9 h.  

Figure 6 is a schematic description of gelling and drug release of HS and HPMC matrix tablets in dissolution tests. The HS matrix tablets could retain the gel matrix structure with resistance to erosion because the swollen particles of HS did not entirely dissolve and maintain the gel-matrix structure. On the other hand, the HPMC gel layer of the tablet surface was gradually eroded because HPMC particles dissolved completely and could not maintain gel structure. Therefore, the rate of dissolution was accelerated by rapid paddle rotation. 

 The effects of PEG on drug-release profiles were investigated to make the formulation of zero-order release matrix tablets. HS or HPMC matrix tablets containing various model drugs (ETZ, APAP, and SSA) with or without PEG, were used in this study. 

Figure 7 shows the dissolution profiles of model drugs from HS and HPMC matrix tablets. Table II shows the formulations of the tablets. The experiments were performed using a USP Type 1 apparatus at a rotation speed of 100 rpm in a JP-2 buffer containing α-amylase in a 5-µg/L concentration. For HS matrix tablets, HS could control the drug-release profiles from first-order to zero-order depending on PEG concentration, regardless of drug solubility. In contrast, HPMC tablets could not provide zero-order release, especially in the case of water-soluble drugs.  

Figure 8 shows the change of tablet weight (see Figure 8a) and water-absorbing capacity (see Figure 8b). The water-absorbing capacity was calculated as a percentage by comparing the tablet weight in the wet state due to water absorption with the tablet weight in the dry state after drying. During 0–2 h, these matrix tablets absorbed a lot of water, and their weights increased. After 2 h, the weights of matrix tablets began to decrease in spite of keeping water absorption. The HS tablet with PEG remarkably absorbed water and lost its weight because the strength of its gel structure weakened. 

Figure 9 is a schematic description of the assumed mechanism of different actions between HS and HPMC matrix tablets caused by promotion of water penetration into tablets by adding PEG. In the case of HS, in the first stage at 0.5–5 h, the hydration of HS particles was promoted, and a strong gel layer was formed,  which contributed to the restraint of drug diffusion. In the second stage of 6 h and after, excess water absorption occurred because the HS water-insoluble elements absorbed a lot of water without dissolving, which contributed to decrease gel strength and to promote gel erosion. Accordingly, the drug-release profiles inclined to zero-order release. In the case of HPMC, the hydration rate of the HPMC particles was not largely affected by adding PEG because the hydration rate was originally rapid. Therefore, the drug-release profiles remained first order regardless of adding PEG. 

Storage stability study of dissolution profiles and of tablets color.

 HS or HPMC matrix tablets containing APAP and MCC with or without PEG were used in this study. Table III shows the formulations of the tablets. These tablets were stored at 40 °C and 75% RH in sealed glass bottles and at 60 °C in polyamine–polyethylene bags. 

Figure 10 shows the dissolution profiles at the initial state and after storage for 6 months. The dissolution tests were performed using a USP Type 1 apparatus at a rotation speed of 100 rpm in a JP-2 buffer containing α-amylase in a 5-µg/L concentration. For HS matrix tablets, no significant change in release profiles was observed. In contrast, those of HPMC changed under the same conditions. 

Figure 11 shows the change of YI. Under conditions of 40 °C and 75 % RH, the YI of the HS matrix tablets slightly changed, although that of HPMC remarkably increased. At 60 °C, the YI of both increased, but the YI of the HS matrix tablets after 6 months was the same level with the initial YI of HPMC tablets. In addition, the YI of the HPMC matrix with PEG remarkably increased. 

The authors conclude that HS can be applied for the development of sustained-release tablets. Experimental data confirmed the following points: 

 Drug release from HS matrix tablets was well controlled under conditions of high ionic strength and high mechanical force 

 The zero-order drug-release profile can be obtained by using a mixture of HS and PEG and is independent from drug solubility 

 The HS matrix tablets show stable drug-release profiles even under accelerated conditions 

The authors examine the use of a novel highly functional pregelatinized starch as a controlled-release matrix excipient.

A Novel Pregelatinized Starch as a Sustained-Release Matrix Excipient

Roller compaction is method of preparing granules for capsules or for tablet formulations. The most common filler–binder excipients used in roller compaction are microcrystalline cellulose (MCC), dibasic calcium phosphate (DCP), and lactose. Studies on the dry granulation of various types of lactose have shown anhydrous lactose to be the best lactose for roller compaction because its brittle nature leads to excellent recompaction properties (1).  

Figure 1 is a schematic of the roller compaction process, including the feed hopper from which the formulation mix is fed by the horizontal feed screw (HFS) to the vertical precompression screw (VPS). The VPS deaerates the powder and increases the density of the powder to approximately its tapped bulk density (TBD) just before it is compacted between the two counterrotating rolls. Beneath the rolls the resulting ribbon is milled by the in-line mill to produce the final granulate product. 

 Figure 1: Schematic of the Chilsonator roller compaction process. HFS is horizontal feed screw; VPS is vertical precompression screw.(all figures are courtesy of the authors.) 

The authors investigated the stability of the roller compaction process and the resulting tableting properties of the granules formulated with anhydrous lactose and with combinations of anhydrous lactose and MCC. 

The materials consisted of the following: anhydrous lactose (SuperTab 21AN, DMV-Fonterra Excipients, Nörten-Hardenberg, Germany), MCC (Pharmacel 102, DMV-Fonterra Excipients), and magnesium stearate (BUFA, Uitgeest, The Netherlands). 

 Roller compaction was performed with an IR520 Chilsonator machine (The Fitzpatrick Company Europe, see Figure 2) with knurled bevelled rolls fed by a horizontal and a vertical feed screw rotating at ~12 and 200 rpm, respectively. The rolls rotated at the minimum speed of 6 rpm (range 6–22 rpm). The minimum speed was used to best monitor the compaction process. The temperature of the ribbons was measured with an infrared thermometer. Subsequent, in-line milling was performed with the FitzMill model D6A system (The Fitzpatrick Company) that incorporated a knife forward rotor set at a speed of 800 rpm with 1-mm screens (#1532-0040). The time needed to process a certain mass of powder was measured to calculate the throughput of each powder blend at a roll line force of 4.2 kN/cm.  

FIigure 2: The Chilsonator IR520 pilot-scale roller compactor (The Fitzpatrick Company Europe). 

 The particle-size distribution (PSD) of the granules was determined with laser diffraction using a Helos system (Sympatec, Clausthal-Zellerfeld, Germany). 

 Granule poured and tapped bulk densities were determined using ~230 mL of powder in a 250-mL graduated cylinder. Volume and mass were measured before and after 1250 taps. 

 Granule and powder blends were compacted with a rotary press (Rotab-T, Luxner, Berlin, Germany) equipped with 9-mm flat beveled punches. Tablets weighing 250 mg were produced in all cases. 

 The tablet-crushing strength was tested on 10 tablets the day following compaction. 

Friability was tested in accordance with 

 The relative standard deviation (RSD) of the weight of 10 tablets was calculated. 

Three placebo blends were roller compacted: 99.25% SuperTab 21AN with 0.75% magnesium stearate; 65% SuperTab 21AN with 35% Pharmacel 102; and 55% SuperTab 21AN with 45% Pharmacel 102. The ribbons did not stick to the roll surface throughout the 20-kg runs. When anhydrous lactose was used as the sole excipient, it was necessary to add some lubricant to prevent the ribbon from sticking to the rolls. The addition of 0.75% magnesium stearate was sufficient. Roller compaction of blends consisting of anhydrous lactose with 35% or 45% MCC required no lubricant to prevent sticking on the knurled roll surface. 

Figure 3: Ribbon temperature versus roll pressure. MCC is microcrystalline cellulose; MgSt is magnesium stearate. 

The temperature of the ribbons was measured during roller compaction. Rolls were cooled with flowing water at a temperature of 14.6 °C. The temperature of the ribbons rose as the process started but stabilized within 5 min for all three blends. Figure 3 shows the stabilized temperature for the three blends at the five roll pressures. The temperature increased with increasing pressure and was slightly higher for blends containing MCC. Increases in temperature are primarily caused by the densification process of the powder but also by work exerted by the vertical precompression screw. The MCC flows less well than SuperTab 21AN and deforms plastically upon compaction compared with the brittle fracture of SuperTab 21AN. These two differences could be the cause of the temperature elevation. 

Figure 4: Particle-size distribution of the SuperTab 21AN 65%, microcrystalline cellulose 35% blend after roller compaction at different pressures and after milling.

A further assessment of the powder blends was made by measuring the throughput. Upon addition of MCC, throughput decreased from 46.0 (0% MCC) to 39.4 (35% MCC) and 41.0 kg/h (45% MCC), which is a reduction of as much as 14%. This decrease was a result of the lower bulk density of the MCC, which shows that at a given roll speed, throughput can be increased by increasing the anhydrous lactose content in the formulation. 

Ribbons formed by roller compaction were milled into granules. For the purpose of this study, mill settings were kept constant for all formulations and roll pressures. Particle-size analysis showed that as roll pressure was increased, the particle size decreased (see Table I and Figure 4). As the ribbons hardened, the milling intensity of the precompacted material increased, resulting in the production of more fines. Optimizing the mill speed and screen size opening may prevent this effect, but this option was not researched further during this project. 

Figure 5: Particle-size distribution (PSD) of the three placebo blends at a roller compactor pressure of 6.3 kN/cm. 

Only small differences were observed among the blends. Figure 5 shows that the particle-size distributions of the various blends are similar after compaction and milling under the same circumstances. Figure 6 shows the resulting poured and tapped bulk densities of the granules made from three different blends. Both poured and tapped densities decreased as MCC was added to the blend. As roller pressures increased, the bulk density of the anhydrous lactose granules decreased slightly. and the tapped density remained constant. 

Figure 6: Poured bulk and tapped densities of the granules and powder blends (0 kN/cm is the powder blend; AL is anhydrous lactose).

The blends containing MCC displayed different behavior. The bulk density remained constant with increasing pressure, and tapped density increased slightly. The net result was a similar increase in Hausner ratio with increasing compactor pressure for all formulations (see Figure 7). 

Figure 7: Hausner ratio versus roll pressure.  

 Figure 8 shows the tablet crushing strength of the tablets compacted from the granules. The tablet crushing strength is compared with that of tablets made from powder blend equivalents of the precompacted granules (i.e., blends that were not roller compacted).  

Figure 8: Tablet crushing strength of tablets compacted at 5, 10, 15 and 20 kN of the roller compacted granules. 

The tablet crushing strength of the tablets increased with increasing compression forces. The granules prepared with 8.4 kN/cm roller compactor pressure capped at compression forces above 10 kN. The tablet crushing strength is, however, more than sufficiently high at this compaction force, as shown in the figure. It was not possible to produce tablets from the granules made at 10.5 kN/cm pressure because of the extremely poor flow of the granules. No attempt was made to improve this situation by adding, for example, a flow agent. The friability of all tablets was low (all below 0.1%). Tablets containing MCC were slightly more robust.  

A decrease in tablet crushing strength occurred between powder blends containing MCC and the granules of the same blend. This decrease between non-roller compacted blend and roller compacted granules was not seen with only anhydrous lactose. The tablet crushing strengths of tablets with and without MCC were similar at equivalent compression forces. 

The weight uniformity of the tablets (see Figure 9) is best when the blend contains MCC and at the lower roller compaction pressures, which may be a result of granule-flow properties. Again, because tablets were not produced using the granules compacted at 10 kN/cm (because of poor flowability), no results for these tablests are portrayed in the figure. 

Figure 9: Weight uniformity relative standard deviation (RSD) of tablets compacted at 5, 10, 15, and 20 kN of the roller compacted granules. 

Anhydrous lactose and blends of anhydrous lactose and MCC are highly suitable for roller compaction. There are beneficial and adverse effects of using blends of anhydrous lactose and MCC compared with anhydrous lactose alone. The addition of MCC decreased the throughput of the roller compactor and increased the temperature of the ribbon. However, roller compaction could be performed without the addition of a lubricant when a blend of anhydrous lactose and MCC was used. In addition, including MCC slightly improved the tablet properties with lower tablet friabilities and improved tablet-weight uniformity. On balance, the blend containing 35% MCC was optimal. 

Increasing roller compactor pressure resulted in granules with wider particle-size distributions and worse flow. In these studies, where milling was not optimized, a pressure of 4.2 kN provided the best balance between particle-size distibution, flow, and tablet properties. 

 is a product and business development manager, and 

 is a research and development scientist, both at DMV-Fonterra Excipients, Nörten-Hardenberg, Germany, 

sander.van.gessel@dmv-fonterra-excipients.com

 is a test facility manager at The Fitzpatrick Company Europe, Sint Niklaas, Belgium.  

 1. S. Hein, J. Langridge, and K. Picker-Freyer, "Evaluation of Various Lactose Types and MCC for Roller Compaction," poster presented at the 2007 AAPS Annual Meeting, San Diego, CA.  

The authors studied the behavior of anhydrous lactose and the combination of anhydrous lactose and the combination of anhydrous lactose with microcrystalline cellulose on a pilot-scale roller compactor.

Roller Compaction of Anhydrous Lactose and Blends of Anydrous Lactose with MCC

Direct compression (DC) is becoming a preferred manufacturing method for tablets. This process is less complicated than dry- or wet-granulation processes and therefore offers shorter product-development timelines and reduced cost to manufacture through the elimination of granulation unit operations. In addition, DC can be used for heat- and/or moisture-sensitive active pharmaceutical ingredients (APIs) because it has a low heat history and does not require water during processing. Excipients used in DC processing, however, must have a combination of properties, including good flow, compressibility, minimal segregation tendency, and good physical and chemical compatibility—a combination not usually associated with controlled-release (CR) excipients. A new family of hypromellose (HPMC) products (Methocel cellulose ethers, Dow Chemical, Midland, MI) was developed that combines these properties with the ability to provide controlled-drug release.     

HPMC products are widely used rate-controlling polymers in oral controlled-release drug-delivery applications. These excipients offer flexibility in formulation and function for preparation of oral solid-dosage forms. However, their application in DC tableting processes is limited in some cases and complicated in others because of their poor powder flow properties. Recent product development efforts have improved powder flow while maintaining suitable compressibility and CR performance and minimizing segregation. 

DC is a tableting process in which a dry blend of ingredients is placed into a tablet hopper and compressed into tablets. It is a much simpler process than wet or dry granulation, eliminating several unit operations and resulting in a more straightforward manufacturing system (see Figure 1). This results in lower manufacturing costs and shorter development times for new formulations. DC has the added advantage of being less harsh on heat- and moisture-sensitive APIs.  

The main parameters for an ideal DC excipient are flowability, compressibility, minimal tendency to segregate, and physical and chemical compatibility with APIs and other ingredients. Reliable flow of pharmaceutical mixtures out of tablet-press hoppers is particularly important for problem-free tablet-press operation and consistent tablet properties. Failure to ensure reliable flow can result in both considerable manual interventions for the tablet-press hopper and poor tablet physical properties, such as high tablet-to-tablet weight variability and tablet hardness. 

Because HPMC has generally poor flow properties and is often present in formulations at high levels (up to 30%), it can have a serious effect on formulation flow in a DC process. As a result, preparing CR formulations with a DC process can be difficult, usually requiring compromises such as flow enhancers or slower production rates. Typically, CR formulations are processed using wet granulation to achieve adequate mixing and improved flow. If the flow properties of HPMC could be improved, the less costly DC process could be used. 

Influence of material properties and environmental factors on powder flow

Powder flow can be a difficult property to quantify because it is influenced by so many factors. Material properties such as particle size and distribution, bulk density, particle shape, moisture content, and cohesiveness all have a role in determining powder flow (1). In addition, environmental factors such as humidity, particle-to-wall interactions, bin and hopper design and dimensions, consolidation time, and load affect powder processing. Measuring powder flow with conventional bench-scale tests can be deceptive because small-scale processes primarily show the effects of particle-to-particle cohesion. If two products have the same chemistry, the particle-to-particle cohesion will be similar. At a larger scale, however, more relevant to production processes, there is an increased influence of gas permeability of the bulk solid. If the gas permeability of the bulk solid is low, the flowing solid is unable to dilate in the conical section of the hopper, a phenomenon referred to as "limiting flow rate."  

Development of DC-grade HPMC using limiting flow rate analysis

The three key measurements used to determine the limiting flow rate are cohesive strength, permeability, and compressibility. During development efforts to improve the flow of CR HPMC, cohesive strength was measured in a shear tester (model RST-01.pc, Dr.-Ing. Dietmar Schulze Schüttgutmesstechnik, Wolfenbüttel, Germany). Permeability and compressibility (bulk density as a function of load) were measured in custom-made equipment. These data were used in a program that solves a series of differential equations to determine the limiting flow rate (2). This technique was used to demonstrate improved flow of the new grades of HPMC for DC, CR applications. This improvement is not the result of decreased particle cohesion (as measured by ring-shear tests), but rather improved permeability of the material as influenced by particle size. Figure 2 shows photomicrographs of the DC-and CR-grade polymers obtained from the image analyzer (RapidVue, Beckman Coulter, Fullerton, CA). The mean particle size of the DC-grade HPMC is more than two times that of the CR-grade HPMC. The limiting flow rate for the DC-grade HPMC was calculated to be 2400 lb/h, while the limiting flow rate for the CR grade HPMC was calculated to be 100 lb/h. Table I compares the physical properties of low- and high-viscosity DC-grade HPMCs.  

Performance of a formulation of metoprolol tartrate and DC HPMC

In studies involving a metoprolol tartrate formulation using DC- and CR-grades of HPMC (see Table II), improvement in flow using the DC grade of HPMC was visually evident at the tablet press (i.e., no manual intervention was required). This resulted in lower tablet-to-tablet weight and hardness variation compared with the CR grade (see Table III). Improved powder flow was also demonstrated 

 testing with an  Aero-Flow powder analyzer (model 0-8030, Amherst Processing Instruments, Hadley, MA). The formulation based on the DC grade exhibited nearly 50% reduction in mean time to avalanche. Dissolution tests of the DC HPMC formulation (see Table II) suggest the same level of controlled-drug release with either DC or CR HPMC (see Figure 3).  

Evaluation of additional formulations containing granular acetaminophen and naproxen sodium also yielded comparable drug-release profiles between DC and CR grades of HPMC (see Figure 4). These two APIs represent drugs with very different physical properties. Granular acetaminophen has poor compressibility and is only sparingly soluble. Its mean particle size is about 400 µ. Naproxen sodium is freely soluble with a mean particle size of 50 µ.  

Further tests showed that 18 months storage of the DC- grade HPMC at room temperature and humidity did not affect controlled-release properties or tablet hardness for an acetaminophen-based formulation. The robustness of the DC HPMC particles was also studied in a V-blender. Experiments were performed by blending for 40 min at both 8-qt and 3-ft

  scales. Only a modest 5% reduction in the particle-size mean was observed.    

DC of CR formulations is possible with the advent of DC-grade hypromellose with improved flow characteristics. After testing in formulations using a wide range of APIs, dissolution profiles and tablet properties of the DC HPMC formulations were shown to be comparable to those of CR-grade HPMC formulations.  

 is a lead application development specialist, 

 is an application laboratory supervisor, 

 is an application development specialist, all at Dow Wolff Cellulosics R&D, The Dow Chemical Company, 1691 N. Swede Road, Larkin Laboratory, Midland, MI 48674, tel. 989.636.4202, fax 989.638.9836, 

*To whom all correspondence should be addressed.  

1.  G.E. Amidon, "Physical and  Mechanical Property Characterization of Powders," in 

Physical  Characterization of Pharmaceutical Solids, Vol 70

, H. Britain Ed., (CRC Press, 1995) pp. 281-320. 

2.  D.A. Craig and R.J. Hossfeld, "Measuring Powder Flow Properties," 

The authors examine the use of a hypromellose-based product as an excipient in a controlled release formulation using direct-compression tableting.

Pharmaceutical Technology-04-01-2009

Using Polymers to Enhance Solubility of Poorly Soluble Drugs

Influence of Superdisintegrants on the Rate of Drug Dissolution from Oral Solid Dosage Forms

A Novel Pregelatinized Starch as a Sustained-Release Matrix Excipient

Roller Compaction of Anhydrous Lactose and Blends of Anydrous Lactose with MCC

A New Hypromellose Excipient for Direct-Compression, Controlled-Release Applications