Added Functionality Excipients: An Answer to

Challenging Formulations
Ashish A. Joshi* and Xavier Duriez

T
Added functionality excipients facilitate the development of novel drug delivery methods and improve processing techniques.
Ashish A. Joshi, PhD, is a project coordinator at Roquette America Inc., 1417 Exchange Street, Keokuk, IA 52632, tel. 319.526.2219, ashish.joshi@roquette.com. Xavier Duriez, PhD, is a pharmaceutical business manager at Roquette Freres (Lestrem, France).
*To whom all correspondence should be addressed.
SENSIENT

ablets and capsules are preferred drug delivery vehicles because they can be precisely dosed, easily manufactured and packaged on a large scale, and can contribute to good patient compliance. Over the years, significant advances in the manufacturing processes of oral solid dosage forms have occurred, including the transition from tablet preparation by wet granulation to direct compression. The development of various added functionality excipients (AFEs), which are used to achieve formulations with desired end-effects, is equally important. The majority of excipients used in the manufacture of solid oral dosage forms have existed for the past two to three decades, many of them continue to be used today for large-scale tablet and capsule manufacturing. Obtaining regulatory approval for the use of new excipients and breaking the tradition of conventional formulation development have been two major hurdles in convincing formulators to incorporate new excipients into their forwww.phar mtech.com

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EXCIPIENTS & SOLID DOSAGE FORMS 2004

Excipients & Solid Dosage Forms mulations. Despite these challenges, Water sorption isotherm at 20 C many new AFEs 10 have been success9 Xylitol fully introduced 8 Mannitol 7 Maltitol and are used in the 6 Sorbitol 5 pharmaceutical in4 3 dustry to date. 2 Compared with ex1 0 0 10 20 30 40 50 60 70 100 isting excipients, 80 90 Relative humidity (%) the improved physical, mechanical, and/or chemical Figure 1: Moisture sorption profiles of various excipients. properties of such AFEs have helped solve formulation unacceptable taste and improve the problems such as flowability, comODTs overall mouthfeel. pressibility, hygroscopicity, palataAn ideal bulk excipient for ODTs bility, dissolution, disintegration, should have the following properties: sticking, and dust generation (1). disperses and dissolves in the The use of conventional tablets is mouth within a few seconds withchallenging to pediatric, geriatric, out leaving any residue and uncooperative patients who masks the drugs offensive taste may have difficulty swallowing and offers a pleasant mouthfeel them. Similarly, swallowing tablets enables sufficient drug loading is problematic when water is unand remains relatively unaffected available or when patients have a by changes in humidity or tempersistent cough or a gag-reflex. perature These problems have been ad preferably directly compressible dressed by the recent introduction and yields sufficiently robust of orally disintegrating tablets tablets to withstand manufactur(ODTs), which also are known as ing, packaging, and transportafast-melt, quick-dissolving, mouthtion, yet disperses quickly on the surface of the tongue. dissolving, or orodispersible tablets ODTs are manufactured using a (2). Upon placement on the tongue, wide variety of technologies such as these tablets rapidly absorb saliva lyophilization, direct compression, and disperse or dissolve within granulation, spray-drying, molding, 1045 s. The dispersed tablet can and the cotton candy process (1). then be swallowed easily without The quick dispersing effect is generwater. Many bulk excipients comated by the excipients ability to abmonly used for conventional tablets sorb water quickly, thus enabling do not fulfill the development rethe water to be wicked away rapidly quirements of an ODT, thus necessitating the use of specific excipients to the tablets core. A tablets rapid dispersion on the surface of the and technologies to mask the drugs
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g water/100 product EXCIPIENTS & SOLID DOSAGE FORMS 2004

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tongue also is facilitated by the use of a superdis700 Xylitol integrant such as Maltitol 600 crospovidone, sodium Sorbitol 500 starch glycolate (SSG), 400 Sucrose or croscarmellose. Al300 though crospovidone 200 typically is used for 100 Lactose ODT formulations, the Mannitol 0 use of SSG may be ad0 10 20 30 40 50 60 70 80 90 Temperature (C) vantageous in some ODT technologies and platforms, especially Figure 2: Aqueous solubility profiles for various excipients. when the final dosage form is small or when wet granulasimplify the process of ODT manution is used. One advantage of infacturing by direct compression. corporating SSG into the intragranular phase during wet granulation is Added functionality its ability to act as a binder when mannitols for ODTs wet and regain its superdisintegrant ODT formulators prefer to use a diefficacy upon drying the granules. rectly compressible mannitol, which Most commercial ODTs have enables the preparation of robust been developed using mannitol as tablets that can withstand processthe bulk excipient of choice. Manni- ing and transportation. Specially tol is overwhelmingly preferred over textured, directly compressible, lactose because of its extremely low spray-dried, or granulated mannitol hygroscopicity (see Figure 1), excelexcipients have been designed to lent chemical and physical drug meet these needs. Processing these compatibility, good compressibility, excipients under defined manufacbetter sweetness, and relatively turing conditions gives them a slower dissolution kinetics. Alhighly porous and friable exterior though both excipients have relastructure (see Figure 3). Upon compression, the structure crumbles tively low aqueous solubilities cominto finer particles, which fill the inpared with other excipients (see terstitial spaces between larger Figure 2) that have acceptable porous particles. Textured excipients palatabilities, the dispersibility of a also provide a satisfactory mouthfeel bulk excipient is more important and are suitable for use in the prepathan its water solubility for a sucration of harder ODTs by direct cessful ODT formulation. Many of compression at low pressure. the initially marketed ODTs were One major drawback of most prepared by the wet granulation of currently marketed ODTs is their mannitol followed by direct comrequirement for specialized and expression. However, added functionpensive packaging to protect them ality mannitols are now available to
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Solubility (g/100 mL) EXCIPIENTS & SOLID DOSAGE FORMS 2004

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Excipients & Solid Dosage Forms during transportation and handling. Furthermore, the consumer must follow specific instructions to remove fragile tablets from specialized Granulated mannitol Spray-dried mannitol blister packs. For example, the consumer is instructed Figure 3: SEM micrographs of textured mannitols. to peel off the blister packs aluminum foil gently Mannitol compression profile and not to push 450 400 Mannitol 400 m the tablet through Mannitol 100 m 350 for removal. SomeMannitol 200 m 300 Coprocessed times the entire 250 mannitol-sorbitol 200 blister pack is 150 sealed in a plastic 100 50 pouch for added 0 10 20 30 0 40 50 60 protection and to Upper punch force (kN) ensure that the tablets retain their quick dispersibility Figure 4: Tableting compression profile for mannitol. even after exposure to unfavorable humidity and small amount of other polyols is temperature conditions. In addione way to create such an excipient. tion, the high friability of these In the case of sorbitols, the presence tablets does not allow them to be of interlocking crystals that are genpackaged and dispensed in regular erated using specific manufacturing bottles. These challenges could be conditions enable strong binding addressed by using a compression and result in a more robust tablet at binder such as a cellulose derivative low compression forces. In addition, in addition to the mannitol powder. the mannitol provides the required Another option is the development dispersibility and mouthfeel for a and optimization of coprocessed successful ODT formulation. The mannitols that exhibit a similar tableting compression profile deflowability and compressibility to picts the tablet hardness generated the directly compressible mannitols using textured mannitols of various and impart low friabilities to the final mean particle sizes and the codosage forms. Thus, the need for spe- processed excipients (see Figure 4). cialized packaging is eliminated. The friability versus compression Coprocessing mannitol with a force profile indicates that the
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Erweka hardness (N) EXCIPIENTS & SOLID DOSAGE FORMS 2004

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tablets exhibit significantly low friFriability versus compression force profile of mannitol ability, even at a 2.5 Mannitol 400 m low compression Mannitol 100 m 2 Mannitol 200 m force (see Figure Coprocessed 1.5 mannitol-sorbitol 5). In addition to 1 contributing to the 0.5 robustness of tablets, the sorbitol 0 10 20 30 0 40 50 60 also imparts a Upper punch force (kN) sweet taste and a unique texture to Figure 5: Friability versus compression profile for mannitol. the mannitol, thereby improving the ODT formulations mouthfeel. The low level of sorbitol required to obtain an added functionality mannitol does not afLoosely associated Compact-matrix fect its pharmaPPS PPS copeial conformity to USPNF stanFigure 6: SEM micrographs of pregelatinized starches. dards, thus offering an advantage with respect to the regulatory reAdded functionality partially quirements. pregelatinized starches The market for ODTs is proAFEs not only facilitate the developjected to increase from $400 milment of novel drug delivery techlion in 2000 to $1 billion before nologies such as ODTs, but also 2005 (3). A major focus for future help to improve the processing of commonly used excipients such as ODT development will be improvpregelatinized starches. PGSs are ing their cost-effectiveness. Alcommercially available in fully though mannitol will continue to pregelatinized and partially pregelabe used as an excipient of choice, tinized starch (PPS) grades dependAFEs can help greatly when develing on the degree of starch gelaoping more-robust and less-friable tinization. PPSs are used as fillers in ODTs. Dispensing these tablets hard gelatin capsules (575%), into conventional bottles will elimbinders in wet granulation tableting inate the need for specialized pack(520%), disintegrants in tablet foraging, thus providing significant mulations (510%), and in direct cost savings. compression tableting (4). However,
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Tablet friability (%) EXCIPIENTS & SOLID DOSAGE FORMS 2004

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Excipients & Solid Dosage Forms Another important processing change for developing an added functionality PPS is to have better control of its particle-size distribution. The decreased friability of a compactmatrix PPS and its 1000 relatively narrow particle-size distribution ensures a reduced level of fine particles (see Figure 7). This change ultimately helps reduce dust generation during tableting or capsule filling and imparts improved flow properties (see Table I). The changes in the composition and particle-size distribution of PPS particles will ultimately influence the dissolution kinetics of the final oral dosage forms. Capsules prepared using a compact-matrix PPS containing a slow-dissolving drug such as acetaminophen exhibit a significantly rapid dissolution of acetaminophen compared with similar capsules prepared using a loosely associated PPS (see Figure 8). Certain changes in the composition of the PPS result in low cold-water solubility and consequently a minimal viscosity increase upon contact with water, and hence a reduced resistance to drug dissolution.

10 9 8 Volume (%) 7 6 5 4 3 2 1 0 1

Compact-matrix PPS Loosely associated PPS

10

100 Diameter (m)

Low fines are dust and better flow

Figure 7: Particle-size distribution of PPSs.

many capsules and tablets that contain currently marketed PPSs as fillers exhibit specific properties that are disadvantageous with respect to increased dust generation during processing and slower drug dissolution. Altering the composition of the starch and optimizing the gelatinization process can add functionality to PPSs and address some disadvantages of using existing PPSs. SEM micrographs of PPSs with various compositions and methods of manufacturing indicate a significant variation in the matrix structure of the starch grains. PPS particles comprising a compact, embedded matrix are significantly less friable than those made of loosely associated PPS particles (see Figure 6).

Table I: Flow properties of PPSs.

Parameter Mean particle size Bulk density Tap density Flow (EP method) Angle of repose
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Compact-matrix PPS 100 m 0.64 g/mL 0.81 g/mL 5s 35

Loosely associated PPS 90 m 0.61 g/mL 0.79 g/mL 7s 41

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Interestingly, the rapid dissoDissolution of acetaminophen from Dissolution of acetaminophen from capsules in pH 5.8 buffer capsules in pH 1.3 buffer lution of aceta100 100 90 90 minophen in 80 80 the presence of 70 70 60 60 a compact50 50 Compact-matrix 40 40 Compact-matrix pregelatinized starch matrix PPS ocpregelatinized starch 30 30 Loosely associated 20 Loosely associated 20 pregelatinized curs in a pHpregelatinized 10 10 0 0 independent 5 0 20 25 30 5 10 15 0 20 25 30 10 15 Time (min) Time (min) manner. Rapid and pHindependent Figure 8: Rapid, pH-independent dissolution of acetaminophen drug dissolufrom a compact-matrix pregelatinized starch. tion is advantageous because it may qualify a new cipients, it is critical that pharmaceuformulation for a biowaiver on clinical tical developers select a reliable exciptesting requirements, according to ient supplier with a broad range of FDA, Center for Drug Evaluation and products and technical expertise as Research guidelines (5). well as a significant global presence. A better understanding of the manufacturing variables and market References 1. S.K. Nachegari and A.K. Bansal, Codemand has lead to the development processed Excipients for Solid Dosage of specific excipients that enhance Forms, Pharm. Technol. 28 (1), 5264 the efficiency of pharmaceutical for(2004). mulations. However, continued glob2. S.R. Parakh and A.V. Gothoskar, A alization in the pharmaceutical inReview of Mouth Dissolving Tablet Technologies, Pharm. Technol. 27 dustry has increased regulatory (11), 92100 (2003). concerns that products developed in 3. C.H. Dubin, Making Bitter Better, one market could be used in other Pharm. Form. and Qual. 5 (2) 2432 parts of the world. To facilitate the (2003). global development of new pharma4. G. Rowley, Starch Pregelatinized, in Handbook of Pharmaceutical Excipiceutical products, formulators must ents, R.C. Rowe, P.J. Sheskey, and P.J. pay close attention to the multicomWeller, Eds. (Pharmaceutical Press, pendial conformity of excipients. London, UK, and American PharmaVarious regulatory issues such as geceutical Association, Washington, DC. netically modified sources of excipi4th ed., 2003) pp. 609611. 5. FDA, Center for Drug Evaluation and ents and their identity-preserved staResearch, Guidance for Industry: tus also are gaining importance. Waiver of In Vivo Bioavailability and Thanks to the commitment and exBioequivalence Studies for Immediatepertise of excipient manufacturers, Release Solid Oral Dosage Forms Based AFEs are now playing an important on a Biopharmaceutics Classification System, 2000, www.fda.gov/cder/ role in addressing the challenges T guidance/3618fnl.htm. P posed by difficult formulations. With the increasing popularity of these exAcetaminophen dissolved (%)

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Acetaminophen dissolved (%)

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