Practical Considerations in Development of Solid Dosage Forms that Contain Cyclodextrin LEE A. MILLER,1 REBECCA L. CARRIER,2 IMRAN AHMED3 1Pfizer, Inc., 2800 Plymouth Road, Ann Arbor, Michigan 48105 2Department of Chemical Engineering, Northeastern University, 457 Snell Engineering Center, Boston, Massachusetts 02115 3Pfizer, Inc., Eastern Point Road, Groton, Connecticut 06340 Received 17 December 2004; accepted 16 October 2006 Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.20831 ABSTRACT: The following is a review of the literature that addresses the use of cyclodextrin in solid dosage forms. Care was taken to exclude physical and chemical characteristics of cyclodextrin, which have been discussed in the literature. A flow diagram is provided to outline the decision-making steps that are involved in the development process. Both preparation of physical mixtures and inclusion complexes are considered. Analytical techniques to determine the presence of inclusion complexes, the effect of other excipients on complex formation, the effect of size limitation of solid dosages forms, powder processing, and storage of solid dosage forms are discussed. ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1691–1707, 2007 Keywords: absorption; solid dosage form; formulation; cyclodextrins; complexation INTRODUCTION absorption. There is extensive coverage of cyclo- dextrin technology in the literature. In fact, a The use of cyclodextrin in the pharmaceutical keyword search in SciFinderTM returns more industry has been extensively studied.1 Moreover, than 30000 potentially relevant references. Many Mosher and Thompson2 listed 20 marketed of the references contain redundant information commercial drug products that benefit in some pertaining to the chemical and physical charac- way from cyclodextrin technology. Cyclodextrin teristics of cyclodextrin. The reader is invited to is incorporated into dosage forms to affect the review any of several comprehensive reviews and Active Pharmaceutical Ingredient (API) or the the references cited within to gain additional formulation as a whole in some manner. This knowledge on cyclodextrin technology.9,10 One could be to enhance stability,3 as a taste mask, as area that we feel the current review literature a manufacturing process aid (filler, binder, only partially addresses is the practical consid- channeling agent, etc.),4 as an osmogen in erations of how to formulate a solid dosage form controlled release pump dosage forms,5–8 and to that contains cyclodextrin. While several articles increase dissolution with the goal of increasing discuss this process, the topic has not recently been comprehensively reviewed. In this review, we intend to satisfy this putative need at the Correspondence to: Lee A. Miller (Telephone: 860-441-6041; exclusion of discussing why cyclodextrin could Fax: 860-686-6209; E-mail: lee.a.miller@pfizer.com) be used, which is readily available from the Journal of Pharmaceutical Sciences, Vol. 96, 1691–1707 (2007) ß 2007 Wiley-Liss, Inc. and the American Pharmacists Association aforementioned references. A few exceptions will JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 1691 1692 MILLER, CARRIER, AND AHMED be made for relevant background information. It The basic development of a solid dosage form is our assumption that the reader has already that contains cyclodextrin is outlined in Figure 1 decided that it is necessary to have cyclodextrin in and is summarized below. Assuming that the the solid dosage form (i.e., to enhance API formulation scientist has determined that cyclo- solubility and bioavailability, stability, taste, dextrin is a necessary component to the formula- etc.) and is now looking to better understand the tion, the first decision is to determine if a physical ramifications of this decision. mixture of cyclodextrin and API is sufficient or if Figure 1. Schematic representation for development of a dosage form that contains cyclodextrin. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 DOI 10.1002/jps CYCLODEXTRIN IN SOLID DOSAGE FORMS 1693 an inclusion complex between cyclodextrin and formulation to improve the material properties API is necessary (Fig. 1A). This can depend on the (Fig. 1I). Furthermore, reformulation may be function of cyclodextrin in the dosage form. The necessary to ameliorate the material property incorporation of cyclodextrin as a physical mixture deficiencies of the formulation. Although con- may be sufficient if the cyclodextrin is functioning ventional and novel granulation techniques as a tableting aid (filler, binder, etc.) or as an should be sufficient to yield a suitable formulation, osmogen. In addition, formation of the complex can the formulator may ultimately need to consider a happen in situ from a physical mixture and provide technology other than cyclodextrin to prepare a increased solubility, increased stability, and taste successful formulation. masking. However, if the role of cyclodextrin is to In this article, we follow the direction of steps increase solubility of the API, it can be advanta- outlined in Figure 1. We first discuss the use geous to use a preformed inclusion complex of the of physical mixtures versus a precomplexed form API and cyclodextrin. of API and cyclodextrin, consider the preparation The formulator must consider the affinity of the of physical mixtures, and then the preparation and API to enter the relatively apolar cavity of analysis of inclusion complexes. We conclude with cyclodextrin (Fig. 1B). The binding constant (K) a review of the literature on manufacture of solid is a measure of this affinity. This value has been dosage forms that contain either physical mixtures shown to range between 0 and 100000 MÀ1, but or inclusion complexes of cyclodextrins. could be greater.11 Burnette and Conors12–14 published mean binding constants of 123, 490, and 525 MÀ1 for a, b, and g-cyclodextrin, res- IS A PREFORMED INCLUSION pectively, which were based on a statistical COMPLEX NECESSARY? analysis. A low binding constant suggests a weakly bound API while a high binding constant suggests A preformed inclusion complex is prepared prior a very strongly bound API. The desired situation is to formulating the tablet or capsule such that the to have sufficient affinity, such as to enhance the API (or a portion of it) is noncovalently bound concentration of total dissolved drug, but still within the cyclodextrin cavity. Techniques to allow for dissociation of the complex followed by accomplish complexation will be discussed in absorption of the API. It is possible to reduce the Section ‘‘Analytical techniques for determination in vivo bioavailability of the API if the binding of inclusion complex formation.’’ A physical constant is too large. In fact, Szejtli4 suggested mixture of API and cyclodextrin is just what its that a K value of >10000 MÀ1 significantly reduces name implies, a product of mixing two species bioavailability due to the inability of the complex to together to yield one mass. There is no chemical dissociate. In this situation, the formulator should association between the API and the cavity of the investigate the use of different cyclodextrins, cyclodextrin. This may be appropriate given the including derivatives, or a different technology specific reason for incorporating cyclodextrin into (Fig. 1C). the formulation (filler, binder, etc.). However, If a preformed complex is not necessary, a many of the advantages of cyclodextrin (taste physical mixture can be prepared by conventional masking, improved stability, enhanced solubility, blending techniques and, depending on the etc.) are not realized until complexation takes material properties of the blend, may be tableted place. Nevertheless, one benefit of using a directly or granulated prior to tableting physical mixture of API and cyclodextrin is the (Fig. 1D,E). On the other hand, if it is necessary ease with which it is prepared. For instance, a to use a preformed complex, an appropriate physical mixture can be manufactured with method of formation of the complex is necessary. conventional formulating equipment and can be At small scale, this is possible using conventional easily scaled. A thorough understanding of the laboratory equipment. However, the need for process of preparing mixtures of pharmaceuti- specialized processing equipment to form the cally relevant formulations is found in the inclusion complex at commercial scale should be literature.15 When the goal is to enhance API considered (Fig. 1F–H). solubility or bioavailability, the literature pre- As with a physical mixture, assessment of the sents differing views on which form (physical material properties of the formulation will help to mixture or preformed inclusion complex) to use. identify if direct compression is an option. If not, The literature suggests precomplexation of the formulator should consider granulation of the cyclodextrin and API will provide significantly DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 1694 MILLER, CARRIER, AND AHMED better enhancement in bioavailability compared to systems containing a physical mixture of cyclo- a physical mixture of API and cyclodextrin. dextrin was recently discussed in a publication by Similar evidence is available that suggests a Biddey et al.24 The researchers support the use of preformed inclusion complex provides for faster cyclodextrins within polymeric drug delivery dissolution kinetics relative to a physical