Exploring Excipient Functionality

This article is part of PharmTech's supplement "Solid Dosage and Excipients 2011."

Excipients play a vital role in drug formulation. Several leading experts share advances in the field. Stuart C. Porter, PhD, senior director, film coating systems and excipients of global pharmaceutical applications, research and development (R&D), at ISP, provides an overview of solid dispersions as a strategy to improve solubility. Firouz Asgarzadeh, PhD, senior technical manager at Evonik, explains the use of predictive systems in pharmaceutical melt extrusion. Phil Butler, technical sales manager, coatings of pharma ingredients and services at BASF, examines film coatings for taste-masking and moisture-protection applications. Jennifer Trevor, PhD, senior business development manager, Ferro Pfanstiehl Laboratories, explores uses of pharmaceutical sugars.

CRISTINA PEDRAZZINI

Solid dispersions overview

Stuart C. Porter, senior director, film coating systems and excipients, global pharmaceutical applications R&D at ISP

It has been estimated that 40–60% of drugs in development have poor bioavailability due to low aqueous solubility, and this is likely to increase in the future with the increased use of combinatorial chemistry in drug discovery targeting lipophilic receptors. Poor bioavailability results in increased development times, decreased efficacy, and increased inter- and intra-patient variability. Thus, improving drug solubility and, hence, bioavailability through formulation and process technology is a formulator's challenge.

Several approaches can be considered for increasing active pharmaceutical ingredient (API) solubility in the gastrointestinal tract (GI), including: particle-size reduction, salt formation, nanoparticles, liquid-filled capsules, conventional formulation techniques with surfactants and/or antinucleating agents, and solid dispersions. The use of solid dispersions/solid solutions in pharmaceutical applications to enhance oral bioavailability was first envisioned in 1961. Only recently, with an increasing number of poorly soluble APIs in development, has interest in using solid dispersions in oral dosage forms gained momentum.

Solid dispersions are molecular (thermodynamically stable solid solutions) and/or colloidal (kinetically stable solid suspensions) dispersions of the amorphous API dispersed in a polymeric matrix. As a result of their morphology and thermodynamic and thermomechanical properties, solid dispersions increase drug surface area, reduce drug crystallinity, and stabilize the system during storage and subsequent administration, in vivo, to inhibit drug recrystallization. Solid dispersions are most practically and most commonly produced in the laboratory through commercial scales via either melt-extrusion or solvent spray-drying process technologies. Each technology for forming a solid dispersion has its advantages and limitations. It has been demonstrated that APIs can be formulated with polymers, such as povidone (e.g., Plasdone, ISP) and copovidone (e.g., Plasdone S-630, ISP) to provide stable solid-dispersions system with excellent shelf-life stability and dramatically enhanced API solubility and bioavailability,

Solubility enhancement, however, does not end with the creation of a suitable solid dispersion of the API. Such a solid dispersion has to be successfully incorporated into the final dosage form. If, for example, the final dosage form is a tablet, the physical stability of the API (in solid dispersion form) has to be maintained throughout the shelf life of that dosage form as well as after ingestion up to the point of drug absorption. Many polymers that are used to create solid dispersions are hydrophilic, and so exposure of the dosage form to environmental moisture can compromise the physical stability of the API, with the result that recrystallization may occur on storage. If the tablet releases the API too quickly on ingestion, especially when drug absorption might be a rate-limiting step, the API may recrystallize in the lumen of the gut before absorption can occur. One remedy, for example, if the API is rapidly released in the stomach, but is not absorbed until after entering the small intestine, may be to delay the release of the API in the stomach with an enteric film coating.

Finally, many oral dosage forms, especially tablets, are likely to be film coated. Because aqueous film coating is the preferred approach today in the global pharmaceutical industry, use of such a process, by potentially adding moisture to the tablet, can again compromise the physical stability of the final product. To mitigate against this risk, one could either employ a non-aqueous coating process (not preferred today) or use a high-solids film coating system (e.g., Advantia Preferred HS Coatings, ISP). By allowing better thermodynamic control of the coating process, the system prevents moisture from penetrating into the tablet core during film coating. Further enhancements could also be achieved by employing a film-coating formulation that exhibits certain moisture-barrier properties.

Solid dispersions (overview) section references

1. J.D. Moser et al., Am. Pharma Review, 11 (6), 68–73, 2008.

2. K. Sekiguchi and N. Obi, Chem. Pharm. Bull. 9 (11), 866–872 (1961).

3. T. Bee and M. Rahman, Manufacturing Chemist 81 (3), 24–25 (2010).

Solid dispersion formulation development using predictive approaches Firouz Asgarzadeh, PhD, senior techical manager at Evonik

Solid dispersion formulations offer effective solutions to the problem of the growing number of poorly soluble drugs (i.e., Biopharmaceutics Classification Scheme (BCS) Class II and IV) in the current pharmaceutical company pipelines. Crystalline drug molecules are converted and stabilized in the amorphous state by the polymeric matrix. Depending upon polymer–drug miscibility, the final product is either a single-phase solid solution with molecular level mixing of the drug molecule or a multiphase matrix containing dispersions of fine particles of crystalline drug within the polymer matrix or a combination thereof. To achieve stable, single-phase solid solutions, selection of polymer–drug combinations with high affinity and appropriate drug-loadings (below saturation concentration) are essential in successful formulation development. Empirical and/or systematic approaches are applied to help with this selection.

Empirical approaches. Empirical trial-and-error methodologies have extensively been used to identify polymer–drug pairs and saturation concentrations in solid-dispersion formulation development. In the empirical approach, binary or ternary blends of drug and polymers, possibly in combination with solublizers, are mixed at several drug loadings. Blends are transformed into solid dispersions via solvent techniques (e.g., film casting, spray-drying, coprecipitation, and freeze-drying) or heating techniques (e.g., comelting, modulated differenetial scanning calorimetry (mDSC), and extrusion). Finally, these prototype formulations are analyzed for stability and amorphous structure content using physicochemical methods (X-ray diffraction, DSC, atomic force microscopy, Raman specroscopy, Fourier transform infrared spectroscopy, nuclear magnetic resonance, assay/degradation products, and/or dissolution). In the second stage of product development, promising formulations are put on accelerated stability to further refine the selection. Considering the number of available polymers for solid–solution preparation and unknown saturation drug loadings for each drug and polymer combinations, numerous empirical trials are needed to identify appropriate concentrations and miscible polymer–drug pairs. Depending upon available drug supplies and resources, such empirical approaches may not be acceptable due to the cost and too long development-time requirements.

To reduce the development cost and to accelerate empirical screening time, high throughput screening (HTS) tools, such as 96-well plate formats with in-tube film casting coupled with in-tube dissolution testing have been developed. These tools can screen hundreds of formulations in a matter of a few weeks. Of course, these HTS tools address the time constraint with empirical approaches. However, to select appropriate combinations, an in-depth understanding of structure–properties relations for drug and polymeric matrix is essential through systematic approaches.

Systematic approaches. Systematic approaches to formulation development of solid dispersions can potentially reduce the number of experiments significantly. In such methods, rather than relying on random mixing of drug and polymers, the initial formulations in the screening studies are selected based upon drug–polymer physicochemical properties, such as solubility parameters, hydrogen bonding, and thermal indicators (e.g., glass-transition or melting temperatures).

One is MemFis (Melt Extrusion Modeling and Formulation Information System, Evonik Pharma Polymers). The system allows pharmaceutical formulators systematic screening of formulations and processing conditions at early stages of solid-dispersion product development to save material and development costs. As the name implies, MemFis has two parts. Formulation Information System uses well- established polymer and organic chemistry group contribution theories to estimate Hansen solubility parameters of drug molecules and polymers. In MemFis calculations, more than 50 chemical group contributions and effects of polar forces (e.g., dipole moments) as well as 40 different hydrogen-bonds on solubility parameters are considered.

MemFis uses the classical Flory-Huggins equation to identify volume fractions of drug–polymer binary mixtures that would minimize the Gibbs free energy of mixing (i.e., saturation solubility limit).

Where n₁ = number of moles of polymer; θ₁ = volume fraction of polymer; n₂ = number of moles of drug; θ₂ = volume fraction of drug; χ₁₂ = Chi parameter, energy to disperse molecules of polymer and drug; R = gas constant; and T = absolute temperature.

MemFis can help in reducing the number of experiments by identifying the pairs of polymer and drug that are potentially miscible and have intrinsically better stability via hydrogen bonding or ionic interactions.

Melt Extrusion Modeling is a process database that contains more than 1300 experiments collected over a decade of pharmaceutical melt extrusion at Evonik. Once lead formulations are selected from the screening studies, the formulation scientists face the challenge of selecting processing conditions for successful melt-extrusion experiments. Process-setting variables are included, but not limited to extruder screw-element design, heating-zone temperatures, energy-input rate, screw speeds, feed rates, and processing-aide selections. The MemFis process database is expanding and is fully searchable and can provide help with initial melt-extrusion process settings.

Case study. Naproxen, a BCS II drug substance, was selected for miscibility estimation using MemFis. Film casting from ethanol solutions and cross-polarized optical microscopy was used to measure the experimental drug-substance solubility in the polymers. Estimated predictions from MemFis calculations and experimentally determined results from film casting are presented in Table I.

Table I: Predictions from MemFis calculations and experimental results from film castings.

These results show that MemFis predictions were reasonably consistent with experimental measurements. The slight underestimation of solubility in Eudragit E PO is likely due to the ionic interactions between the drug and the polymer, which are not considered in the calculation model. The overestimations for a few of the polymers are most likely due to the fact that such polymers could engage in intramolecular hydrogen bonding rather than intermolecular bonding with the drug and that not all hydrogen-bonding sites on the polymer backbone are available to interact with the drug.

MemFis predictions help in reducing the number of experiments by identifying polymer–drug formulations with higher potential for miscibility and stability through hydrogen bonding formation. The calculations, therefore, can be used to screen many compounds for miscibility and solid-solution formation minimizing API use and development time.

Solid dispersion (predictive approaches) section references

1. C.Y. Wu and L.Z. Benet et al., Bull. Technique Gattefosse 99, 9–16 (2006).

2. F. Qian et al., Int. J. Pharm. 395 (1–2), 232–235 (2010).

3. Lauer et al., Pharm. Res. 28 (3), 572–584 (2011).

4 A. Shanbhag et al. Int. J. Pharm 351 (1–2), 209–218 (2008).

Pharmaceutical sugars

Jennifer Trevor, PhD, senior business development manager, Ferro Pfanstiehl Laboratories

The International Pharmaceutical Excipients Council (IPEC) provides 13 broad categories of excipients for solid dosage forms based upon function: binders, disintegrants, fillers, lubricants, glidants, compression aids, colors, sweeteners, preservatives, suspending/dispering agents, film-formers/coatings, flavors, and printing inks. Key features of excipients used in solid dosage manufacturing have traditionally been based upon flowability and particle size, among other characteristics.

One factor to consider when choosing an excipient is the desired release characteristics, whether it be immediate, sustained, or modified release (1). Quick-dissolving tablets have garnered more attention of late, especially with regard to using trehalose, a disaccharide of glucose, in solid-dosage formulation (2). One important feature that make this an attractive excipient for this usage is that it does not absorb water readily in the crystalline state, which lends to enhanced stability and reduced stickiness (3). Ohtake et al. recently wrote an extensive review article on the unique usages of trehalose in solid dosage forms. The authors noted that the information on trehalose-containing pharmaceuticals in the US is limited; however, there are a number of patents claiming the use of trehalose in solid-dosage applications.

Another attractive attribute of trehalose is the avoidance of Schiff bases from the reaction of aldehydic sugars with primary and secondary amines, such as what occurs with lactose. Trehalose does not react with amino groups and therefore is an attractive choice as a bulking agent. Additionally, anhydrous trehalose is not subject to undue hardness, such as lactose, and dissolves readily. Thus, the potential for developing trehalose in solid-dosage formulations is expanding.

Pharmaceutical sugars section references

1. V. Joshi, Drug Delivery Technol. 2 (6), 1–4 (2002).

2. S. Ohtake and J. Wang, J. Pharm. Sci. , DOI: 10.1002/jps.22458, Feb. 18, 2011.

3. K. Takeuchi and N. Banno, Fragrance J. 7 (7), 39–47 (1998).

Film coatings in taste-masking and moisture protection

Phil Butler, technical sales manager, coatings of pharma ingredients and services at BASF

Coating of solid oral dosage forms is an effective and economical route to providing moisture protection and taste-masking properties to moisture sensitive and bitter- tasting active ingredients (1). To achieve both properties using the same polymer, chemical functionality needs to be designed to provide not only insolubility in saliva (pH 6.8–7.2) for protection from unpleasant taste, but also reduced affinity to water for moisture protection.

Methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion (Kollicoat Smartseal 30 D, BASF SE) provides this dual functionality along with a fast release of active ingredients in the stomach (see Figure 1). The diethylaminoethyl basic functional groups result in an insoluble polymer at basic and neutral pH values and a quick-dissolving polymer at pH values below 5.5 (2).

Figure 1: Solubility of methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion.

The performance as a taste-masking agent was evaluated by a human-taste panel. This assessment correlates very well with results from in vitro dissolution tests at pH 6.8 (see Figure 2), which proved to be a reasonable substitute and therefore suitable for quality-control purposes. The results in Figure 3 demonstrate that coating levels of 4–5 mg/cm² of a Kollicoat Smartseal 30 D based formulation can effectively mask the unpleasant taste of quinine hydrochloride tablets.

Figure 2: Quinine hydrochloride dissolution in ph 6.8 phosphate buffer.

A robust film-coating formulation is needed in the compression of coated particles into tablets as with taste-masking of pediatric, chewable acetaminophen tablets. Maintaining coating integrity and eliminating particle-coating failure are important for intact coating functionality after compression. To determine optimal use level for similar applications with methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersions, cast films were plasticized with tributyl citrate, triethyl citrate, and acetyltriethyl citrate at levels between 10 and 25% for elongation at break comparison. Elongation at break values of approximately 100% were attained using 13–15% plasticizer content range, which provides sufficient flexibility for coated particle compression applications (3).

Figure 3: Comparative taste panel results with quinine hydrochloride tablets.

Acetaminophen crystals, with a mean particle size of 300 µm, were coated using a methyl methacrylate and diethylaminoethyl methacrylate copolymer (6:4) coating consisting of 8% talc, 0.4% colorant, 1.51% triethyl citrate (15% relative to polymer content), 33.33% copolymer, and 56.67% water (20% solids content). Coated samples were taken at 7.5, 15, 22.5, and 30% weight gain. A coating weight gain of 7.5% (w/w) provided significant taste-masking with immediate dissolution at pH 1.2 (see Figure 4).

Figure 4: Acetaminophen release at pH 1.2.

With regard to moisture protection, the use of a lipophilic plasticizer and pigments can optimize the protective properties of a methyl methacrylate and diethylaminoethyl methacrylate copolymer film coating. Vapor permeability studies performed on sprayed films containing 15% triethyl citrate (w/w based on polymer) and increasing levels of talc (0–40%) reveal a decreasing level of moisture permeability with increasing talc content (see Figure 5).

Figure 5: Impact of talc on vapor permeability.

As an example, sorbitol, with its highly hygroscopic properties, was compressed into tablet cores containing 49.75% sorbitol (Neosorb P 60 W, Roquette), 49.75% Ludipress (BASF), and 0.5% magnesium stearate to a hardness of 110 N. The tablets were coated with a 34.66% methyl methacrylate and diethylaminoethyl methacrylate copolymer film also containing 1.35% tributyl citrate (13% relative to polymer), 0.26% butylated hydroxytoluene (2.5% relative to polymer), 8.00% talc, and 55.73% water (20% solids content total). Sample tablets taken at coating levels of 0, 3, 4.5, 6, 9, 12, and 20 mg/cm² and placed on 30 °C and 70% stability showed an increase in moisture-barrier properties with an increase in coating weight gain (see Figure 6).

Figure 6: Moisture uptake of sorbitol tablets at 30 °C and 70% relative humidity.

Based on the physicochemical properties of methyl methacrylate and diethylaminoethyl methacrylate copolymer dispersion, optimized protective film coatings can be formulated to provide taste-masking and moisture-barrier properties for bitter and moisture-sensitive active ingredients.

Film coating section references

1. Z. Ayenew et al., Recent Patents on Drug Deliv. & Formul. 3 (1), 26–39 (2009).

2. BASF SE, Kollicoat Smartseal Technical Information (Ludwigshafen, Germany), Jan. 2011.

3. K. Kolter, F. Guth, and M. Angel, "Physiochemical Characteristics of a New Aqueous Polymer Designed for Taste-Masking and Moisture Protection," presented by BASF at AAPS Annual Meeting and Exposition, New Orleans, Nov, 14–18, 2010.

Formulation development and manufacturing

Despite the intensification of biologic-based drug development, solid dosage forms are the mainstay in the pharmaceutical industry. Changing regulatory requirements, increased cost pressures, and the need to innovate for better product life-cycle management and product differentiation, are leading pharmaceutical companies to seek ways to improve development and manufacturing.

Pharmaceutical Technology recently held an webcast to more fully examine the current and future direction in formulation development, dosage forms, and manufacturing of solid-dosage products, including the role of continuous processing and FDA's quality by design (QbD) initiative. Participating in the webcast, which was held Mar. 1, 2011, was Robin H. Bogner, R.Ph., Ph.D., associate professor of pharmaceutics in the Department of Pharmaceutical Science at the University of Connecticut, to discuss technical advances in solid-dosage formulations and dosage forms. John Groskoph, senior director of new products CMC, global chemistry manufacturing and controls at Pfizer, discussed QbD in solid-dosage manufacturing.

External development and manufacturing also are becoming more important in a pharmaceutical company's strategy. In another webcast, Pharmaceutical Technology examined how to optimize outsourcing CMC development and manufacturing. The webcast, which was broadcast on Mar. 8, 2011, featured Clive V. Bennett, nonexecutive chairman of Halo Pharmaceutical, Gregg Brandyberry, CEO of Wildfire Commerce and senior advisor of A.T. Kearney Procurement and Analytic Solutions, and former vice-president of procurement of global systems and operations at GlaxoSmithKline, and George Bobotas, PhD, and chief scientific officer at Halo Pharmaceutical. On-demand viewing on both webcasts are available in the multimedia section at PharmTech.com.