Sakae Obara

Evaluation of Hypromellose Acetate Succinate (HPMCAS) as a Carrier in Solid Dispersions

The utility of hypromellose acetate succinate (HPMCAS), a cellulosic enteric coating agent, as a carrier in a solid dispersion of nifedipine (NP) was evaluated in comparison with other polymers, including hypromellose (HPMC), hypromellose phthalate (HPMCP), methacrylic acid ethyl acrylate copolymer (MAEA), and povidone (PVP). An X‐ray diffraction study showed that the minimum amount of HPMCAS required to make the drug completely amorphous was the same as that of other cellulosic polymers, and less than that in dispersions using non‐cellulosic polymers. Hypromellose acetate succinate showed the highest drug dissolution level from its solid dispersion in a dissolution study using a buffer of pH 6.8. This characteristic was unchanged after a storage test at high temperature and high humidity. The inhibitory effect of HPMCAS on recrystallization of NP from a supersaturated solution was the greatest among all the polymers examined. Further, the drug release pattern could be modulated by altering the ratio of succinoyl and acetyl moieties in the polymer chain. Our results indicate that HPMCAS is an attractive candidate for use as a carrier in solid dispersions.

Dry coating: an innovative enteric coating method using a cellulose derivative.

A novel enteric coating method was developed. This method involves direct feeding of coating polymer powder and simultaneous spraying of plasticizing agent, without either organic solvent or water, using a centrifugal granulator, fluidized bed, or tablet-coating machine. For film formation, a curing step was then necessary; this involved spraying a small amount (3-8% of core weight) of water or hydroxypropyl methylcellulose solution, followed by heating. Hydroxypropyl methylcellulose acetate succinate was used as the enteric coating polymer, and a combination of triethyl citrate and acetylated monoglyceride was used for plasticization. The coated beads and tablets were evaluated for gastric resistance, intestinal disintegration, and stability, in comparison with beads and tablets from a conventional aqueous coating with the same enteric polymer. The new method required a higher coating amount for gastric resistance compared with the conventional coating, but the processing time was dramatically reduced. The results show that this dry coating method is applicable to the preparation of enteric-coated beads and tablets using commercially available lab-scale apparatus.

Influence of processing variables on the properties of free films prepared from aqueous polymeric dispersions by a spray technique

Abstract A novel method for the preparation of free films from aqueous polymeric dispersions by a spray technique is reported. The apparatus included a spray gun, rotary drum and a temperature controlling system. The influence of spray rate and processing temperature on the mechanical properties of free films prepared from aqueous dispersions of Eudragit© L 30D-55, and L 100-55 (methacrylic acid-ethyl acrylate copolymer), Shin-Etsu AQOAT® (hydroxypropyl methylcellulose acetate succinate), Aquateric® (cellulose acetate phthalate) and Aquacoat® (ethyl cellulose), plasticized with triethyl citrate, was investigated. The processing temperature was monitored using a telemetric system. Reproducible free films were obtained from the five polymers using this apparatus. The tensile strength and elongation of films of the two Eudragit® latex dispersions, having a minimum film formation temperature (MFT) less than 20°C, were not influenced by spray rate or processing temperature between 30 and 40°C. The mechanical values of free films from Shin-Etsu AQOAT® were significantly decreased at a slower spray rate, but processing temperature did not affect film properties. This polymeric dispersion contained larger particles than the acrylic dispersions and the free films had a low MFT. The Aquateric® dispersion, having a high MFT, contained larger particles than the acrylic latexes and produced films at high spray rates and slow drying conditions. The drying temperature significantly influenced the elongation properties of the films. The mean tensile strength of free films from Aquacoat®, a high-MFT latex, was slightly higher at higher processing temperature, but this was not significant. The spray rate did not alter the mechanical properties of films prepared from this pseudolatex.

Supersaturation, nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: Polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs

The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit® EPO and AQOAT® AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat® 603 and Kollidon® VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat® 603>Eudragit® L-100-55>AQOAT® AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation.

Stability assessment of hypromellose acetate succinate (HPMCAS) NF for application in hot melt extrusion (HME)

HPMCAS is a widely used polymer in the pharmaceutical industry as an excipient. In this work, the physicochemical stability of HPMCAS was investigated for hot melt extrusion (HME) application. The reduction in zero rate viscosity (η0) of the polymer with the increase in temperature was determined using rheological evaluation prior to HME processing. The energy of activation for AS-MF determined by fitting Arrhenius model to the temperature dependent reduction in η0 was found to be slightly lower than that for the other grades of HPMCAS. Glassy yellowish HMEs were obtained using Haake Mini-Lab MicroCompounder operated at 160, 180, and 200°C and 100, 200, and 300 rpm for all the grades at each temperature. Various physicochemical properties of HPMCAS such as glass transition temperature, semi-crystalline nature, solid state functional group properties, moisture content, and solution viscosity were not significantly affected by the HME processing. The most significant change was the release of acetic and succinic acid with the increase in HME temperature and speed. The free acid content release due to HME was directly proportional to the speed at lower operating temperatures. AS-LF was found to be the most stable with the lowest increase in total free acid content even at higher HME temperature and speed. Although the dissolution time was not affected due to HME for AS-LF and AS-MF grades, it was notably increased for AS-HF, perhaps due to significant reduction of succinoyl content. In conclusion, the HME processing conditions for solid dispersions of HPMCAS should be based on the acceptance levels of free acid for the drug and the drug product.

Molecular weight determination of hypromellose acetate succinate (HPMCAS) using size exclusion chromatography with a multi-angle laser light scattering detector

The molecular weight of hypromellose acetate succinate (HPMCAS), a polymer used for enteric coating, was determined by means of size exclusion chromatography with a multi-angle laser light scattering detector. The weight-average molecular weight (Mw) of several lots and grades ranged approximately from 17000 to 20000, and the number-average molecular weight (Mn) was around 13000. The inter-day precision of measurement, in terms of the coefficient of variation, was less than 5%.

Critical Design Features of Phenyl Carboxylate-Containing Polymer Microbicides

ABSTRACT Recent studies of cellulose-based polymers substituted with carboxylic acids like cellulose acetate phthalate (CAP) have demonstrated the utility of using carboxylic acid groups instead of the more common sulfate or sulfonate moieties. However, the pKa of the free carboxylic acid group is very important and needs careful selection. In a polymer like CAP the pKa is approximately 5.28. This means that under the low pH conditions found in the vaginal lumen, CAP would be only minimally soluble and the carboxylic acid would not be fully dissociated. These issues can be overcome by substitution of the cellulose backbone with a moiety whose free carboxylic acid group(s) has a lower pKa. Hydroxypropyl methylcellulose trimellitate (HPMCT) is structurally similar to CAP; however, its free carboxylic acids have pKas of 3.84 and 5.2. HPMCT, therefore, remains soluble and molecularly dispersed at a much lower pH than CAP. In this study, we measured the difference in solubility and dissociation between CAP and HPMCT and the effect these parameters might have on antiviral efficacy. Further experiments revealed that the degree of acid substitution of the cellulose backbone can significantly impact the overall efficacy of the polymer, thereby demonstrating the need to optimize any prospective polymer microbicide with respect to pH considerations and the degree of acid substitution. In addition, we have found HPMCT to be a potent inhibitor of CXCR4, CCR5, and dual tropic strains of human immunodeficiency virus in peripheral blood mononuclear cells. Therefore, the data presented herein strongly support further evaluation of an optimized HPMCT variant as a candidate microbicide.

Properties and Applications of Hypromellose Acetate Succinate (HPMCAS) for Solubility Enhancement Using Melt Extrusion

The development of bioavailable solid dispersions requires the use of secondary materials for stabilizing the amorphous dispersion while also enhancing dissolution and solubility of the new chemical entity. With the increased use of amorphous dispersions, hypromellose acetate succinate (HPMCAS) has emerged as a commonly used excipient for formulation design. This unique material, originally designed to enhance thermoplastic properties of cellulosics, can be used to enhance the solubility of many poorly soluble amorphous products. This chapter details the properties of HPMCAS that make it a beneficial material for use in solid dispersion formulation, with a specific focus on relevant properties for melt extrusion.

Developing a stable aqueous enteric coating formulation with hydroxypropyl methylcellulose acetate succinate (HPMCAS-MF) and colloidal silicon dioxide as anti-tacking agent

&NA; The purpose of this study was to use statistical design of experiments to develop a stable aqueous enteric coating formulation containing stabilizing excipients, such as polyethylene glycol that can minimize hydroxypropyl methylcellulose acetate succinate aggregation and minimize spray‐nozzle clogging at elevated processing temperatures. The mechanisms of stabilization (i.e. charge stabilization and molecular interactions) were studied by performing zeta potential and FTIR studies. Electrostatic stabilization by sodium lauryl sulfate and hydrogen bonding by polyethylene glycol provided dispersion stability and yielded a stable aqueous coating formulation that prevented spray‐nozzle clogging. An enteric coated tablet with better gastric resistance was obtained by incorporating fumed silica (Aerosil® R972) as the anti‐tacking agent instead of talc. Dissolution testing on the riboflavin enteric coated tablets showed a good enteric release profile without releasing riboflavin in 0.1 N HCl, and completely disintegrating within 10 min in phosphate buffer (pH 6.8).

Impact of formulation excipients on the thermal, mechanical, and electrokinetic properties of hydroxypropyl methylcellulose acetate succinate (HPMCAS)

&NA; Hydroxypropyl methylcellulose acetate succinate (HPMCAS) has been widely used in amorphous solid dispersions and as an enteric coating polymer. Under aqueous coating conditions and at elevated coating temperatures, HPMCAS particles tend to aggregate and clog the spray‐nozzle, hence interrupting the coating process. This research focused on how plasticizers and surfactants, excipients used for aqueous coating, affect the properties and stability of HPMCAS. This information would be useful in identifying suitable excipients for developing a stable HPMCAS aqueous enteric coating formulation. Triethyl citrate was found to be the most compatible plasticizer with HPMCAS, and displayed suitable thermal and mechanical properties. PEG 4000, the co‐plasticizer, provided dispersion stability by yielding a dispersible sediment without aggregation at the elevated processing temperatures. Zeta potential measurements indicated sodium lauryl sulfate (SLS) could be used as a potential stabilizing agent at concentrations above its critical micelle concentration (CMC). This study facilitated the understanding of the HPMCAS aggregation mechanism, in addition to identifying suitable stabilizing agents. These stabilizing excipients could potentially be used to develop a stable aqueous coating formulation that does not exhibit polymer aggregation and nozzle clogging during the coating process.