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 M1, but or inclusion complexes of cyclodextrins. could be greater.11 Burnette and Conors12–14 published mean binding constants of 123, 490, and 525 M1 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 M1 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 mixture systems to facilitate erosion by functioning as a of API and cyclodextrin or the API alone.16–20 channeling agent and promoting diffusion of water Savolainen et al.21 reported poor bioavailability into the device. This increase in erosion rate can from glibenclamide and the physical mixture of lead to faster drug dissolution relative to a device glibenclamide with hydroxypropyl-b-cyclodextrin with slower erosion. (HP-b-CD) relative to inclusion complexes based Okimoto et al. compared the release rate of on in vivo dog studies. Their data is reproduced in testosterone from inclusion complexes of test- Table 1 and shows an absolute bioavailability for osterone and either SBE-b-CD or HP-b-CD, with crystalline glibenclamide and the physical mix- physical mixtures of testosterone and either ture with HP-b-CD of approximately 14.8%. SBE-b-CD or HP-b-CD, and physical mixtures of Inclusion complexes with glibenclamide and testosterone with a mixture of lactose and fruc- b-cyclodextrin, HP-b-CD, and sulfobutyl ether- tose.5 They investigated the API release from b-cyclodextrin (SBE-b-CD) show absolute bio- powder formulations, core tablets, and tablets availability of 72.4, 84.3, and 80.1%, respectively. covered with a semipermeable membrane using In this case, the physical mixture formulation was an osmotic pump device. The data showed that not statistically better than the crystalline API, complexes that were preformed via lyophilization while the preformed inclusion complexes were (freeze drying) showed faster and more complete significantly improved. API release than the physical mixture formula- Other research has shown that formulating API tions, both as powders and compressed tablets. and cyclodextrin as a physical mixture can lead to The mixture of sugars showed the slowest release dissolution rate enhancement. Rao et al.22 showed rate as anticipated. However, when a film coat was that dissolution rate enhancement can be obtained applied to the device, the release rates of testoster- when using a physical mixture of one from the SBE-b-CD formulations (both and cyclodextrin in a matrix tablet. In fact, the preformed and physical mixture) were nearly data suggested that complexation happens in situ identical. This implies that the API and cyclodex- during hydration, and complex formation between trin need to be held in close proximity to one SBE-b-CD and prednisolone in the bulk medium is another, as in the case of a film-coated dosage form, not significant. Literature from Cydex showed no if formulated as a physical mixture. In the case of significant difference in the in vitro release of a an immediate release dosage form, the species physical mixture of SBE-b-CD with methylpred- with higher solubility (cyclodextrin) could nislone relative to a preformed complex.23 How- diffuse away from the less soluble species (API) ever, this conclusion was based on in vitro and formation of the inclusion complex could be performance data and an in vivo correlation was reduced. not reported. One explanation for increased drug The apparent lack of dependence on precom- dissolution in polymeric matrix drug delivery plexation for film-coated dosage forms suggested

Table 1. Pharmacokinetic Parameters of Glibenclamide (GBA) in Plasma after Oral Administration to Beagle Dogs (mean SEM, n ¼ 4) and Cyclodextrin Amounts Present in Various Formulations21

Cyclodextrin Amount Absolute Added (mg) to d Treatment Cmax (ng/mL) Tmax (h) MRT (h) Bioavailability (F,%) Solubilize 3.0 mg of GBA Crystal GBA 83.9 4.7 4.5 0.5 6.5 1.1b 14.7 3.4 — Physical mix 117.4 19.1 3.5 0.5 4.7 0.4a 14.8 2.6 200 GBA/b-CD 499.9 84.0a,b 2.0 0.7a,b 4.6 0.3a 72.4 4.2a,b 300 GBA/HP-b-CD 610.0 80.4 2.5 0.5a 4.5 0.4a 84.3 4.2 a,b,c 200 GBA/SBE-b-CD 569.0 50.8a,b 1.8 0.3a,b 4.1 0.5a 80.1 5.1 a,b 1200

aSignificantly different from the value for the capsules containing crystalline GBA. bSignificantly different from the value for the capsules containing physical mixture. cSignificantly different from the value for the capsules containing GBA/b-CD (p < 0.05 ANOVA, Fisher’s PLSD test). d F ¼ AUC0-inf oral/AUC0-inf iv 100%.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 DOI 10.1002/jps CYCLODEXTRIN IN SOLID DOSAGE FORMS 1695 by this work may change when the material is Reference [26]. This process involves preparation metered from a ‘‘push-pull osmotic tablet.’’ In this of aqueous solutions (buffered or unbuffered) with case, the core material is essentially extruded from an excess of a low solubility drug in combination the tablet orifice as a suspension and complexation with solutions of increasing concentration of may take place in the hydrating gel layer of the cyclodextrin. Equilibrium is established between extrudate. While this may provide for improved solid drug (D) and dissolved (complexed or free) complexation relative to a system where the drug. components are not held in close proximity, the D ! D þ D ð1Þ complexation may not be as efficient as in a system solid free complex where the API and cyclodextrin are held within a Therefore, as complex is formed between free film-coated dosage form as implied by Okimoto drug and cyclodextrin, the concentration of free et al. In the case of a ‘‘push-pull osmotic tablet,’’ a drug is replenished by dissolution of solid drug. preformed inclusion complex of API with cyclo- Following an appropriate equilibration time, dextrin will most likely provide greater enhance- which can range from minutes to days and should ment in the dissolution of API relative to a physical be determined on a case-by-case basis,27,28 the mixture. solutions are filtered or centrifuged and UV-Vis In summary, data supporting the use of cyclo- spectroscopic analysis is performed. The phase dextrin as a physical mixture as well as a solubility diagram is prepared by plotting the preformed inclusion complex to enhance API total drug concentration on the y-axis and the solubility and improve bioavailability is present total cyclodextrin concentration on the x-axis. in the literature. From a formulator’s point of view, From this plot, the binding constant is deter- it is easier to prepare a formulation containing a mined for a 1:1 complex by: physical mixture. Furthermore, when developing dosage formulations where the core components K ¼ðslopeÞ=S0ð1 slopeÞð2Þ are held in close proximity during hydration or the where S is the intrinsic solubility of the sub- effects of dilution are minimized (e.g., controlled 0 strate. There is a large dependence of K on the or sustained release dosage forms), a physical value determined for S , which depending on the mixture may perform well. However, the litera- 0 solubility of the API, can be near the lower limit of ture supports the use of preformed inclusion detection. If the resulting phase-solubility dia- complexes in a majority of cases. In the context of gram is nonlinear and shows positive deviation, it the literature and in our experience, a preformed is known as type A and suggests a ratio of complex will provide for improved bioavailability P cyclodextrin to drug greater than 1. Alternatively, relative to a physical mixture in both immediate a negative deviation from linearity is known as release and controlled release dosage forms. type AN. The origin of this case has not been well defined within the literature. Higuchi and Con- nors29 speculated that it may come about from THE PHASE-SOLUBILITY METHOD FOR solvent effects or self-association of cyclodextrin DETERMINATION OF BINDING CONSTANTS at high concentrations. It is also possible to combine a drug and cyclodextrin with a result of One of the important parameters of inclusion little to no solubility enhancement and, at a complexes is the affinity the guest molecule has solubility limit, for precipitation of the inclusion for the cyclodextrin cavity. The affinity, or complex to occur. These systems have been binding constant (K), of an API for cyclodextrin labeled as type B and B , respectively.30 should be determined early in development if an S I inclusion complex is found to be necessary. There are several methods by which to determine PREPARATION OF SOLID the binding constant between cyclodextrin (or INCLUSION COMPLEXES derivatives of) and a substrate. The majority of work has been completed using the principles There are two basic methods used to prepare of the phase-solubility method popularized by inclusion complexes of drug and cyclodextrin. The Higuchi and Connors25 with spectroscopic detec- first is known as the kneading process and tion. The technique has been thoroughly dis- requires conventional formulating equipment cussed within the literature and most recently (e.g., low and high shear mixers). The inclusion by Loftsson with historic references cited within complex yield is usually high and can be scaled-up

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 1696 MILLER, CARRIER, AND AHMED to meet the demands of late-stage clinical studies 508C or fluidized-air drying is acceptable.31 Once or commercialization because of its use of conven- the desired moisture level is reached, the cake is tional equipment. The second method is known as milled to the appropriate particle size. the co-precipitation method and yields a highly pure and crystalline inclusion complex. However, The Co-Precipitation Method the processes in this method are relatively longer compared to the kneading method, use As is in the kneading method, a slurry is first nonaqueous solvents, and can promote solvent- prepared by mixing the cyclodextrin with water cyclodextrin cavity competition. Scale-up of and adding a predissolved solution containing the the co-precipitation process can be challenging API. However, unlike the kneading method, the due to the longer processing times and use of mixture is allowed to dissolve completely using nonaqueous solvents. Both the kneading and co- rapid stirring, further dilution, and possibly precipitation methods, as well as suitable drying heating. Precipitation of the inclusion complex is process, are described below.1 It should be noted encouraged by either slow cooling of the solution that there is limited information in the literature or drop wise addition into a solvent that regarding quantitative extent of complex forma- maintains a low inclusion complex solubility. tion upon processing, and there are analytical Alternatively, the pH of the solution can be limitations to determining the extent of com- adjusted to result in precipitation of the plexation, which will be addressed in Section complex.32 The precipitate is then washed with a ‘‘Formulating with cyclodextrin and cyclodextrin suitable solvent and dried. The oven-drying inclusion complexes.’’ method or fluidized-air drying methods are again applicable. The Kneading Process Other Methods of Preparation The kneading process is similar to the wet- granulation process performed by formulation Two other methods discussed in the literature scientists to improve manufacturability and include a dry grinding method and a novel process blend uniformity. However, a larger amount of referred to as a steam-aided granulated method. solvent (aqueous/organic) is used in the kneading In the dry grinding method, no solvents are used. process relative to wet-granulation. Depending on Instead, the cyclodextrin and API are combined the desired scale, the kneading process can be and ground with a mortar and pestle.17 The yield performed in a mortar and pestle or planetary or of inclusion complex is variable33,34 and may be high-shear mixers. The process involves combin- dependent on the formation of hydrogen bonds35 ing the cyclodextrin with sufficient water to yield between cyclodextrin and drug or on the water a slurry or homogeneous paste. The API is added content of the cyclodextrin, which can act as a to this slurry as either a solid or a predissolved medium for inclusion to take place. aqueous solution and the components are mixed. The dry grinding method has been met with Gan et al.8 studied the effect of kneading time on limited success. Lin et al.33 investigated the complex formation and found that, for a glipizide/ physicochemical properties of crystalline acetami- b-cyclodextrin system, continued mixing after 2 h nophen, warfarin, indomethacin, diazepam, and did not further affect the inclusion complex yield. hydrocortisone acetate with b-cyclodextrin follow- This work was done at small scale with a mortar ing grinding in a ceramic ball mill for 24 h. Their and pestle. At a larger scale, mixing time may results showed that the dissolution rate of these have a greater affect on complexation yield. The drug-cyclodextrin systems was higher following slurry is rinsed with a suitable solvent to aid the grinding process relative to a physical mixture in removal of excess or un-complexed API. The of drug and b-cyclodextrin (unground), crystalline resulting preparation is then dried by any of drug, or ground drug. However, when compared several drying methods. If available, microwave to complexes formed by lyophilization, the lyophi- drying in the granulation vessel is desirable due lized complexes showed the highest dissolution to its efficiency and reduced product handling. rates. Infrared spectroscopy suggested that acet- Otherwise, drying in an oven between 20 and aminophen was the only API that formed a complex with b-cyclodextrin following grinding. 1The lyophilization process for inclusion complex formation The dissolution rate increase seen in the will be discussed as a drying step. other APIs was attributed to loss of crystallinity

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 DOI 10.1002/jps CYCLODEXTRIN IN SOLID DOSAGE FORMS 1697 during the grinding process and interaction with verify the extent of inclusion complex formation. b-cyclodextrin during the dissolution test. There are several analytical techniques available The steam-aided granulated method involves to determine complex formation. For example, the combination of high energy grinding in the phase solubility, high-performance liquid presence of steam to form the inclusion complex.36 chromatography (HPLC),40 circular dichroism Cavallari et al. showed that for a piroxicam/ (CD), nuclear magnetic resonance (NMR), mass b-cyclodextrin system the steam-aided granulat- spectroscopy (MS), X-ray powder diffraction ing process provides for improved drug dissolution (XRPD), differential scanning calorimetry and improved pharmacokinetics relative to other (DSC), thermogravimetry (TG), solid state 13C methods of preparation (freeze drying and spray NMR, UV-Vis spectroscopy, Fourier transform drying). It is believed that steam-aided granula- infrared spectroscopy (FT-IR), FT-Raman tion provides a higher diffusion rate into the spectroscopy, and differential solubility have been powder, a more favorable thermal balance during cited in the literature.41,42 Nevertheless, all of the drying step, and a stronger more efficient these methods are not suitable for all complexa- binder relative to liquid water even when an tion systems. For instance, in the solution state inclusion complex is not formed.37 NMR, CD, UV-Vis, HPLC, and MS are obvious choices. However, for determination of complex formation in the solid state, one may choose Methods of Drying from thermal analysis (DSC, TG), solid state 13C In addition to the methods mentioned above the NMR, or XRPD, etc. Unfortunately, the processes lyophilization (freeze-drying) or spray-drying, involved in manufacture of the solid inclusion methods are also well known processes for drying complexes often results in an amorphous mixture inclusion complexes. In the literature, these two and can confound spectroscopic and X-ray results. processes are differentiated from the kneading In these instances, it can be difficult to accurately and co-precipitation methods and are often distinguish between free cyclodextrin, free referred to as distinct methods for inclusion drug, and inclusion complexes.42 Several of the complex preparation. However, the initial steps aforementioned analytical techniques are dis- to complex formation using lyophilization or cussed below in more detail. spray-drying are similar to those of kneading and co-precipitation. For instance, lyophilization Thermal Analysis and Differential Solubility involves completely dissolving the cyclodextrin and drug in an aqueous solution, which is Thermal analysis methods including Differential similar to co-precipitation. However, instead Scanning Calorimetry (DSC) and Thermogravi- of allowing the complex to precipitate from metric Analysis (TGA) are suitable methods for solution, the solution is frozen (408C) and dried determination of the interaction between drug under vacuum to yield a product with relatively and cyclodextrin molecules. The process of low residual water content.31,38 Similarly, the complexation results in a unique molecule with spray-dried product is prepared from solution but different physical properties relative to the free is atomized into a drying chamber (758C) and drug or cyclodextrin. These physical properties collected as a dried solid material.39 The main include melting point, heat capacity, heats of disadvantages of the lyophilization and spray- reaction, kinetics of decomposition, and changes drying processes are that the equipment is in the flow properties.43 The inclusion complex is expensive, can occupy a considerable amount evidenced through DSC by a loss of the endo- of laboratory space, and require specialized thermal melting peak of crystalline drug. This technical knowledge. technique is usually supplemented with a second- ary method (spectroscopy) to show that the loss of a drug related melting peak is due to formation of ANALYTICAL TECHNIQUES FOR an inclusion complex with the drug rather than DETERMINATION OF INCLUSION thermal degradation or a loss of crystallinity. COMPLEX FORMATION DSC is commonly thought to be a qualitative technique. However, Giordano et al.44 conducted In this section, preparation of solid inclusion research on complexes of paracetamol-b-cyclodex- complexes was discussed. At this point of trin and -g-cyclodextrin and showed, the formulation development, it is necessary to by DSC, evidence of inclusion complex formation

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 1698 MILLER, CARRIER, AND AHMED and determined the stoichiometric ratio of the spectrum of the individual components and those complexes. They determined that for DSC to be of the physical mixture were identical suggesting useful in this capacity, it was necessary for that the physical mixing process was not the inclusion complex to be easily formed and sufficient to yield the inclusion complex. the fusion temperature of the API to be lower than Similarly, Kim et al.47 utilized 1H-NMR and and not significantly affected by the cyclodextrin. Monte Carlo simulations to determine that the Van Hees et al.42 discussed a method for ion pair of ziprasidione mesylate (Geodon1) more determining concentrations of free and favorably forms an inclusion complex with SBE- bound piroxicam from prepared piroxicam-b-cyclo- b-CD relative to the dissociated ionic species. In dextrin complex using the method of differential addition, two-dimensional 1H-NMR is useful in solubility and compared these results with the further elucidating the orientation of API in the results of conventional DSC. In the differential cavity of cyclodextrin. Kim et al. used nuclear solubility method, a mixed solvent system of overhauser enhancement spectroscopy (NOESY) water–acetonitrile (1:1, v/v) was used to measure to confirm the structure of the complex predicted the total drug concentration from a solution of by Monte Carlo simulations between ziprasidone complex and free API. The free piroxicam concen- mesylate and SBE-b-CD. Roselli et al.48 utilized tration was determined by mixing the complex rotating-frame nuclear overhauser enhancement with anhydrous acetonitrile. This solvent spectroscopy (ROESY) to enhance the dipolar dissolved any free piroxicam, but not the complex. interaction between protons of the cyclodextrin The researchers found that both methods provided with the protons of nimesulfide that were residing for accurate results and a linear relationship within the cavity and structurally characterize between the dependent variable of the specific the inclusion complex. method (absorbance or temperature) and free Carbon-13 NMR spectroscopy has been utilized piroxicam content. The differential solubility in determining complexation and stoichiometry of method allowed for a lower level of detectability inclusion complexes. The technique has wide and improved precision over conventional DSC. applicability because it can be used on solid When TGA is used in conjunction with DSC, one samples or samples dissolved in aqueous medium. can quantify the amount of API involved in the Bettinetti et al.49 utilized solution 13C-NMR to inclusion complex by monitoring the melting determine the stoichiometric ratios of naproxen points of the noncomplexed drug, cyclodextrin, with the three naturally occurring cyclodextrins inclusion complex, and the amount of drug and several chemically modified b-cyclodextrins substrate lost during heating. Again, the melting (hydroxypropyl-b-cyclodextrin, hydroxyethyl-b- point of the drug substrate needs to be less than cyclodextrin and methyl-b-cyclodextrin). The that of the inclusion complex.45 researchers used this information to support molecular modeling of the inclusion complex. Nuclear Magnetic Resonance Circular Dichroism Proton and 13C-NMR have been used to determine the formation of inclusion complexes as well as to Circular dichroism results when the speeds of the give an idea of how the drug substrate is two electric vectors of polarized light become positioned in the cyclodextrin cavity. The protons unequal when passed through an optically active in the cyclodextrin cavity and on the drug substance due to differences in absorptivities molecule undergo a chemical shift during of the light at a specific wavelength causing complexation that can be resolved by 1H- circularly polarized light to become elliptically NMR. Ghorab et al.46 used 1H-NMR and mole- polarized.43 Within a specific absorption band of cular modeling to determine the orientation of polarized light, a change in the sign of the angle of ibuprofen in b-cyclodextrin and aid in explaining rotation (þ to or vice versa) is known as the the observed differences in in vitro release Cotton effect. This effect is observed in solutions data between complexed material and physical of cyclodextrin when the chromophore of the drug mixtures. The orientation of ibuprofen in substrate is associated with the cyclodextrin the cyclodextrin cavity was approximated by cavity. Information about the orientation of the closely observing the differences in chemical API substrate in the cyclodextrin cavity is gained shifts between physical mixtures and inclusion by monitoring the sign and intensity of the complexes. Results showed that the 1H-NMR induced Cotton effect. That is, according to

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 DOI 10.1002/jps CYCLODEXTRIN IN SOLID DOSAGE FORMS 1699 the Kirkwood-Tinoco theory, a positive induced behavior of paracetamol, which is known to circular dichroism Cotton effect will result when undergo compression by brittle fracture. They the API is aligned parallel to the axis of symmetry studied four different formulations composed of of the cyclodextrin and a negative induced Avicel PH 101 (5%), Aerosil 200 (1%), Ac-Di-Sol circular dichroism Cotton effect will result if it is (1%), magnesium stearate (1%), and 460 mg of aligned in a perpendicular orientation.10 Kim either paracetamol, a physical mixture of et al.47 used circular dichroism to show that the paracetamol and b-cyclodextrin, or inclusion counter ion of several different salt forms of complexes of paracetamol and b-cyclodextrin (1:1 ziprasidone is involved in the inclusion complex ratio, w/w). The inclusion complex was prepared with SBE-b-CD. The researchers plotted the by the kneading and spray dried methods. induced ellipticity at a specific wavelength as a Flat-faced tablets with a diameter of 12 mm and function of different molar ratios of drug and an average weight of approximately 522 mg were SBE-b-CD to determine the stoichiometry of the prepared. Tests on the tablets containing a inclusion complex, which was evidenced by the physical mixture of b-cyclodextrin with para- maximum observed ellipticity at a molar ratio cetamol showed a brittle fracture compression of 1. mechanism similar to a b-cyclodextrin free for- Up to this point, we have discussed the use of mulation. The paracetamol-b-cyclodextrin formu- physical mixtures or inclusion complexes of API lations that were formed by kneading or solid and cyclodextrin, how to prepare them, and in the spray dried dispersion methods showed evidence case of the latter, how to test for complexation of plastic deformation, which is consistent with (Fig. 1A–H) Next, we will present topics specific the compression behavior of cyclodextrin and cor- to formulating with solid oral dosage forms of relates to the work of Shangraw et al. (discussed physical mixtures and inclusion complexes below). (Fig. 1I). Furthermore, our Material Assessment Labora- tory assessed the material properties of g-cyclo- dextrin (Cavamax1, Wacker) and showed that FORMULATING WITH CYCLODEXTRIN AND it has a balance of material attributes and CYCLODEXTRIN INCLUSION COMPLEXES deficiencies.53 The attributes of the material include a high tensile strength and high bonding From Figure 1, we are at the stage in develop- strength, which promote bond retention during ment where the formulation scientist will decide decompression and result in improved tablet on how to process the formulation and ultimately hardness. On the contrary, it was found to exhibit manufacture the solid dosage form. Assessment of poor bond formation during compression, high the material properties is paramount in this brittleness, which results in brittle fracture decision-making process. Given acceptable mate- under mechanical stress, and marginal flow- rial properties, it may be possible to directly ability. Effective ways of dealing with these compress the formulation. However, less than deficiencies is to maintain a low level of desirable material properties will dictate granula- g-cyclodextrin in a direct compression formula- tion or possibly re-formulation. Other factors to tion, include excipients with superior properties in consider include limitations of tablet size, the the formulation, or further process the formula- effect of excipients on formation of the inclusion tion (e.g., granulation). complex, and storage of the final product. Munoz-Ruiz et al.54 characterized the particle and powder properties of a,b, and g-cyclodextrins Material Assessment and hydroxypropyl-b-cyclodextrin. A summary of Important mechanical properties to consider for their work is shown in Table 2. Their method of solid dosage form manufacturing include flow, particle size analysis was based on digitalized density, dynamic hardness, elastic modulus, and images of scanning electron micrographs (SEM), tensile strength. In addition, brittle fracture, which is somewhat limited but an accepted method bonding, and viscoelastic behavior are important of visual analysis. Particle sphericity was based on to tableting performance.50,51 The literature a shape factor defined as the ratio between the offers a limited discussion on the material proper- equivalent diameter of the sphere having the same ties of cyclodextrin. Tasic et al.52 utilized scanning area and the equivalent diameter of the sphere electron micrographs (SEM) to investigate the having the same perimeter. Percent water influence of b-cyclodextrin on the compression content was determined by Karl Fischer titration.

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 1700 MILLER, CARRIER, AND AHMED

Table 2. Particle and Powder Properties of Cyclodextrins

Approx. Mean Sphericity Shape Water as Water at Cyclodextrin Type Particle Size (mm) Value Uniformity Value Received (%) 60% RH (%) Alpha 30 30.5 4.3 9.26 10.71 Beta 150 28.5 3.5 13.48 14.48 Gamma 15 31 2.5 7.69 10.55 HPBCD 12 33.5 1.6 4.75 10.68

The average particle size was similar for HP-b- uniformity and flow. Both of these manufacturing cyclodextrin and g-cyclodextrin (12 and 15 mm, processes have been explored and can be found in respectively), 30 mm for a-cyclodextrin, and the literature for formulations containing cyclo- 150 mm for b-cyclodextrin. It should be mention- dextrin as a physical mixture and an inclusion ed that others have found the mean particle size of complex. b-cyclodextrin to be significantly less (28 mm), albeit based on optical microscopy rather Direct Compression Process than SEM.55 The increasing order of particle spheri- city was found to be b-cyclodextrin

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 DOI 10.1002/jps CYCLODEXTRIN IN SOLID DOSAGE FORMS 1701 low degree of brittleness. This finding is contrary strength was measured as a function of compac- to our observations with g-cyclodextrin. Never- tion pressure and showed that b-cyclodextrin was theless, particle size is an important physical more compressible than dicalcium phosphate and characteristic to monitor when using a significant spray dried lactose independent of manufacturer. percentage of cyclodextrin in a formulation or The compressibility of the Amaizo lot approached when considering a change in lot or supplier. that of microcrystalline cellulose. It was not In addition, Pande and Shangraw58 showed surprising that, upon investigation by scanning that yield pressure for the Kleptose1 DC increased electron microscopy, this lot showed a higher with increasing punch speed. However, the poro- degree of lamination within the crystalline parti- sity did not change as a function of compaction cles, which would result in stronger tablets due to pressure, which suggests that Kleptose1 DC under- more extensive deformation under the stress of goes plastic deformation similar to Kleptose1. compaction. On the contrary, the Roquette lot was The surface area of Kleptose1 DC was shown found to be less compactable and showed a lesser to be significantly higher than that of Kleptose1 degree of lamination in the individual crystalline over a range of particle size fractions. The increa- particles. The researchers also showed that se in surface area was found to be a result of b-cyclodextrin compacts require a relatively low surface cracks, which helped to explain the level (0.1–0.5%) of lubricant to minimize the increased tendency for Kleptose1 DC to be more ejection force. There was no significant difference compressible. in the ejection forces observed at 0.5 or 1.0% Saleh59 published results on the use of lubricant. However, these studies were conducted b-cyclodextrin as a direct compression excipient. on an instrumented single-station press with a b-cyclodextrin performed as a good direct compres- formulation composed of nearly 100% b-cyclodex- sion excipient relative to common direct com- trin. As various excipients are added to the pression excipients (microcrystalline cellulose, formulation, or compaction is performed on a spray crystallized dextrose maltose, dicalcium high-speed rotary press, the reliance on lubrica- phosphate dehydrate, corn starch, mannitol, and tion should be expected to increase. crystalline sorbitol) based on particle size and distribution, flowability, bulk density, and hygro- scopicity. The disintegration properties were Granulation Process reported as poor based on a disintegration time of 43 min. Saleh concluded that this slow disin- If direct compression of the formulation is not tegration time could be ameliorated by inclusion feasible, one should consider the granulation of a disintegrate. However, this result is process. The granulation process involves the somewhat arbitrary, since it is based on a tablet intentional build-up of small particles into larger containing 99% b-cyclodextrin and 1% magnesium agglomerates through the use of mechanical force stearate, which is not representative of an actual and binders. Generally, through the process of formulation. granulation, specific material deficiencies are Shangraw et al.55 characterized the tableting ameliorated allowing for a larger percentage of properties of b-cyclodextrin from four different the deleterious material to be incorporated into suppliers.2 The formulations studied were pre- the formulation. The benefits include improved pared as a direct compression or wet granulation of flow, densification, and a more uniform particle physical mixtures and inclusion complexes with size. There is a lack of published research in . Their results suggested the particle the area of dry granulation with cyclodextrin or size from the four different suppliers was not inclusion complexes containing cyclodextrin. significantly different, but, based on the Carr’s However, there is substantial data on the use of Index, b-cyclodextrin from Roquette showed wet granulation, either as a way to form an increased ability to flow relative to the other inclusion complex or as a way to process a brands. Nevertheless, all of the b-cyclodextrin preformed complex. The literature suggests that compacts were tableted on a single-station press wet granulation of a preformed complex will not due to restrictions in adequate flow. The tensile result in rapid over-granulation to form exces- sively large agglomerates or loss of complexation 2 The suppliers are Nihon Shokohin, Kako Co. Ltd. Tokyo, between the drug and cyclodextrin. Shangraw Japan; Amaizo, American Maize Products, Co., Hammond, 55 Indiana; Roquette Corporation, Gurnee, Illinois; and UR et al. showed that for a complex of progesterone Industry, Inc., Montville, New Jersey. and b-cyclodextrin, a granulation could be made

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 1702 MILLER, CARRIER, AND AHMED with a resulting compatibility better than that of complex formation are possible, including a physical mixture. However, the same reference competition between PVP and progesterone also shows that inclusion complexes can for the cyclodextrin cavity. A comparison of form spontaneously during wet granulation of a the binding constants for these two guest physical mixture of cyclodextrin and API. The molecules with b-cyclodextrin would be helpful in effects of solvent type, use of binder, mixer type, determining if competition for the binding site was and lubrication level will be discussed below. a factor. In preparation to conduct wet granulation Among the three types of mixers used, trials, the appropriate solvent, binder, and mixer (planetary, V-blender with dispersing bar, and type need to be identified. For instance, Ghorab high shear), Shangraw et al. found that high-shear et al.60 showed that for an ibuprofen/b-cyclodex- mixers were less efficient at yielding the inclusion trin system the granulation solvent has an effect complex in situ due to more efficient and extensive on the binding constant for the complex. The distribution of granulating solvent relative to apparent stability constants for the ibuprofen/ planetary mixers. The irony is that an over-wet b-cyclodextrin inclusion complex, when formed by granulation could yield over-agglomerated the wet granulation process, increased with the material resulting in a failed batch, but would following solvents: ethanol > water > isopropanol. also increase the amount of inclusion complex Shangraw et al.55 conducted wet granulation formed if the formulation components had suitable experiments on a noncomplexed mixture of pro- solubility in the granulation solvent. For this gesterone and b-cyclodextrin as well as on a reason, formation of the inclusion complex before precomplexed material. An inclusion complex of wet granulation should be considered. In addition, 60% purity was achieved through aqueous wet a balance between solvent quantity, drug and granulation of a noncomplexed mixture. Use of an cyclodextrin solubility, and rate of solvent distri- alcohol–water (50% by volume) solution slightly bution should be sought. reduced the amount of inclusion complex formed Shangraw et al.55 investigated the ejection (55%), most likely due to the decreased solubility of forces that resulted when tablets were compressed b-cyclodextrin in alcohol.55 Overall, the results from wet granulated physical mixtures or wet suggested that the percent progesterone dissolved granulated inclusion complexes, which contained from tablets prepared by wet granulation of a 10% progesterone. The ejection forces were physical mixture or wet granulation of an significantly reduced in the granulated complex. inclusion complex were similar.55 This was due to This suggests a reduced dependence on lubrication the physical mixture undergoing inclusion com- level most likely because a larger percentage plexation during both the wet granulation process of progesterone was protected within the and the dissolution test. However, in all dissolu- b-cyclodextrin cavity in the inclusion complex tion studies, the directly compressed physical formulation relative to the physical mixture mixture lagged behind that of the wet granulated formulation, and therefore, the formulation con- inclusion complex or wet granulated physical taining more complexed progesterone did not have mixture. the same lubrication requirements. This finding The practice of incorporating a binder as a suggests that cyclodextrin may be a useful means dry material or predissolved component in the to ‘‘hide’’ formulation components that have less granulation solvent is common. The literature than desirable material properties. suggests that cyclodextrin can function as a binder in a wet granulated or physical mixture formula- Size Limitations of Solids Dosage Forms tions.61 However, Shangraw et al.55 reported that, in the case of progesterone, the ability for b- One reason that incorporation of cyclodextrin into cyclodextrin to function as a binder is significantly a solid oral dosage form is met with reluctance is reduced when it is involved in an inclusion the limitation due to tablet size, and thus, the complex. Furthermore, they showed that limit on the total amount of cyclodextrin and API addition of polyvinyl pyrrolidone (PVP) as a binder that can fit inside a tablet of acceptable size and reduced the tendency for inclusion complex for- weight. Depending on why cyclodextrin is present mation during wet granulation. The researchers in the dosage form, the total deliverable dose is no suggested this was due to decreased solvent longer limited to only the API, but now can be availability. While this is a feasible explanation, thought of as the sum of the API and the other reasons for the reduction in inclusion cyclodextrin (i.e., if cyclodextrin is to increase

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 DOI 10.1002/jps CYCLODEXTRIN IN SOLID DOSAGE FORMS 1703

API solubility). Szejtli62 notes that the total mass affected by the presence of other excipients in of a tablet should not exceed 500 mg, which would the formulation. Gan et al.8 performed phase- significantly limit the cyclodextrin to drug ratio. solubility tests on glipizide and b-cyclodextrin We feel that a tablet with a mass between 800 mg into saturated solutions of lactose, sodium and 1 g is a more practical limitation. Figure 2 chloride (NaCl), and mannitol. Their results depicts the theoretical limitation on loading for an showed significant differences in the binding 800 mg tablet with an API molecular weight of constant of glipizide to b-cyclodextrin depending 500 g/mol. The effect of cyclodextrin molecular on which saturated solution was used. Water and weight is exemplified through the comparison of a saturated solution of NaCl showed the lowest b-cyclodextrin (m.w. 1135 g/mol) and SBE-b-CD binding constant values of 965 M1 and 924 M1, (m.w. 2160 g/mol). At low drug loading (20 mg), respectively. The binding constants into a a cyclodextrin:API ratio of approximately 2is saturated solution of mannitol or lactose were achieved for both b-cyclodextrin and SBE-b-CD. 1521 M1 and 5159 M1, respectively. The However, as the drug load is increased to >20 mg authors did not mention possible reasons for the amount of SBE-b-CD that can fit in the tablet the observed range of binding constants or and still allow adequate space for excipients is provide data on the solution pH, ionic strength, significantly limited (cyclodextrin:API ratio 2). or ionization state of glipizide. However, there has Since b-cyclodextrin has a lower molecular weight been a significant amount of research done on the relative to SBE-b-CD, it is possible to obtain a effects of water-soluble polymers on solubility dose of approximately 35 mg at a cyclodextrin:API enhancement of cyclodextrin complexes.66–69 The ratio equal to 2. Depending on the reasons for reasons presented to explain this occurrence may including cyclodextrin in the formulation, a low also help to explain the observations of Gan et al. cyclodextrin:API ratio may negate the benefits of Teresa and Mura reported a marked increase in its use. The range of cyclodextrin to API ratio in the solubility of naproxen as a tertiary system marketed products varies from 3:1 to 15:1, but with b-cyclodextrin and carboxymethylcellulose studies have been published where the ratio was sodium (NaCMC), which was attributed to the as low as 0.3:1 to as high as 92:1.21,63–65 These ionization potential of NaCMC. When other high amounts of cyclodextrins help to explain why polymers (hydroxypropylmethyl cellulose, poly- a majority of marketed products are injectables ethylene glycol 6000, and polyvinylpyrrolidone rather than solid dosage forms. K30) were added to solutions that contained naproxen/b-cyclodextrin complexes at low levels (0.1% to 0.25% w/v), an increase in the stability Effect of Excipients on Inclusion Complex Formation constants (6% to 50% increase compared to no The formulation scientist should consider how the polymer system) was observed.69 This increased in situ formation of the inclusion complex could be complexation strength may be attributed to

Figure 2. Relationship between molar ratio (cyclodextrin:API) and dose for an 800 mg tablet.

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 96, NO. 7, JULY 2007 1704 MILLER, CARRIER, AND AHMED interactions with the intramolecular bonds within by Shangraw et al.55 At a relative humidity the cyclodextrin system or surrounding aqueous similar to that in a controlled laboratory environ- environment.70 ment (21–41% RH), there was little to no change Based on the above information, the presence of in the tablet crushing strength over 15 days other excipients in the dosage form at low levels (2.63 MPa tensile strength at 140 MPa com- (polymers) or at saturated levels (mannitol/ pression force). However, as the relative humidity lactose) could affect the binding constant between was increased to 52% RH and then 90% RH, the cyclodextrin and API. crushing strength of the tablets was reduced to One of the typical uses of inclusion complexes 2.06 MPa and 1.31 MPa at 140 MPa compression with cyclodextrin is to increase the solubility of force, respectively. These data correlate with the poorly soluble drugs. Often, low levels (0.5–2.0%) work of Giordano et al.72 who showed a significant of a surfactant are added to the dissolution loss of tablet hardness upon rehydration of a receptor solution during in vitro development thermally stressed b-cyclodextrin compact over a testing to further enhance drug solubility. 60-day period. This raises the concern that competition between Giordano et al. performed crushing strength the drug molecule and the surfactant for the experiments on flat-faced tablets containing cyclodextrin cavity could affect drug solubility. either b-cyclodextrin, anhydrous b-cyclodextrin, Veiga and Ahsan71 performed a study on the effect or b-cyclodextrin that was dried and allowed to of dissolution of mequitazine in the presence of rehydrate under ambient conditions. The results b-cyclodextrin and two surfactants, Brij-35 and are summarized in Table 3 and show an increase in sodium lauryl sulfate (SLS), into distilled water. the crushing strength of the tablets containing The results suggested no change in drug dissolu- rehydrated b-cyclodextrin. As expected commer- tion rate when b-cyclodextrin was added to a cially available b-cyclodextrin showed an increase solution of Brij-35 below its critical micelle in crushing strength from approximately 50 N to concentration (CMC). When b-cyclodextrin was approximately 100 N as tablet weight was added to a solution of Brij-35 above its CMC, a increased from 250 mg to 300 mg, respectively. decrease in drug dissolution rate resulted. The However, the crushing strength of anhydrous dissolution efficiency of mequitazine increased in b-cyclodextrin that was allowed to readsorb the presence of Brij-35, but it remained unchanged water to different levels (up to 14.5%) reached a or decreased when b-cyclodextrin was added to the maximum of approximately 300 N over the same system. This suggested an interaction between weight range. The crushing strength decreased as Brij-35 and b-cyclodextrin. In addition, a decrease a function of storage time (60 days) for the of mequitazine dissolution efficiency was noted compacts containing rehydrated material. The when SLS and b-cyclodextrin were combined with hypothesis put forward was that water rapidly the drug at a ratio of 1:1 (SLS: b-cyclodextrin). adsorbed onto the surface of the anhydrous However, dissolution of mequitazine improved as b-cyclodextrin resulting in increased tablet the amount of b-cyclodextrin increased relative to hardness. In addition, the formation of solid SLS (1:2 and 1:3). This behavior may be due to an phases with low crystallinity could have played a interaction between SLS and b-cyclodextrin at a role. However, upon storage, the water migrated ratio of 1:1. into the crystal lattice of the b-cyclodextrin result- ing in the formation of hydrates and a decrease in Storage of Tablets Containing Cyclodextrin tablet hardness. The interaction between water The effect of relative humidity on crushing and the crystal lattice resulted in a loss of cohesive strength of b-cyclodextrin compacts was reported properties. The formulation scientist is advised

Table 3. Crushing Strength of b-Cyclodextrin Tablets as a Function of Weight and Percent Water Content

Tablet Weight Type Tablet Weight (mg) (mg, after Rehydration) Crushing Strength (N) Water Content (%) Anhydrous b-CD 250 250 15 0 250 300 300 14.5 b-CD 250 NAa 50 14.6 300 NAa 100 14.6

aNot applicable.

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