A classification system for tableting behaviors of binary powder mixtures

Review

A classification system for tableting behaviors of

binary powder mixtures

Changquan Calvin Sun

*

Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota

A R T I C L E I N F O Article history:

Received 1 September 2015 Received in revised form 22 October 2015

Accepted 13 November 2015 Available online 2 February 2016

A B S T R A C T

The ability to predict tableting properties of a powder mixture from individual compo-nents is of both fundamental and practical importance to the efficient formulation development of tablet products. A common tableting classification system (TCS) of binary powder mixtures facilitates the systematic development of new knowledge in this direc-tion. Based on the dependence of tablet tensile strength on weight fraction in a binary mixture, three main types of tableting behavior are identified. Each type is further divided to arrive at a total of 15 sub-classes. The proposed classification system lays a framework for a better understanding of powder interactions during compaction. Potential applications and limi-tations of this classification system are discussed.

© 2016 The Author. Production and hosting by Elsevier B.V. on behalf of Shenyang Phar-maceutical University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Keywords: Powder Mixture Tensile strength Tabletability Classification system Compaction

1.

Introduction

Tabletability is the capacity of a powdered material to be trans-formed into a tablet of specified strength under the effect of compaction pressure[1,2]. It may be represented by a plot of tablet tensile strength vs. compaction pressure. Since phar-maceutical tablets usually contain multiple ingredients, the ability to predict tabletability of a powder mixture from indi-vidual components is of both fundamental and practical importance to pharmaceutical industry.

A mark of empirical formulation development is the choice of formulation composition based on personal preference and previous experience with other drugs. Unfortunately, the same excipient matrix that worked for some active pharmaceutical

ingredients (API) may not be appropriate, much less optimum, for another API because the properties of different APIs can differ profoundly and drug loading likely is also different. Al-though it is possible to prepare a series of powder mixtures for a new drug candidate and quantify their tabletability in turn, this screening approach is time and resource intensive for for-mulation development. In contrast, forfor-mulation design based on an understanding of tableting performance of drug and in-dividual excipients as well as their interactions would be much more efficient. In this context, the ability to reliably predict tabletability of a mixture based on that of constituting com-ponents is critical. Hence, in addition to the consideration of stability, flowability, and other important pharmaceutical properties, the selection of excipients should be also based on their mechanical properties. This approach allows better

* 9-127B Weaver-Densford Hall, 308 Harvard Street S.E., Minneapolis, MN 55455, USA. Tel:+1 612 624 3722; fax: +1 612 626 2125. E-mail address:[email protected].

Peer review under responsibility of Shenyang Pharmaceutical University. http://dx.doi.org/10.1016/j.ajps.2015.11.122

1818-0876/© 2016 The Author. Production and hosting by Elsevier B.V. on behalf of Shenyang Pharmaceutical University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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accommodation of unique properties of the API, rather than by trial and error, to deliver an overall superior powder mixture (formulation) that can be processed and manufactured ro-bustly. This is particularly important for truly realizing the quality-by-design.

Efforts have been made to study tableting properties of mix-tures[3–21]. At a high level, these studies can be divided according to the tableting property they focused on, e.g., com-pressibility (porosity vs. pressure)[22]and compactibility (tensile strength vs. porosity (or relative density))[23,24]. Compress-ibility and compactCompress-ibility are fundamental properties that influence powder tabletability[25,26]. However, tabletability is of practical importance because it describes the relationship between the process parameter, i.e., pressure, and an impor-tant property critical to tablet quality, i.e., mechanical strength. Therefore, the ability to predict tableting performance of mix-tures from those of individual components is useful, but not yet attained. Accurate predictions would require the access to a large set of data that accurately describes tabletability of ex-cipients and their mixtures. A useful step in achieving such a goal is to develop a classification system for tableting behav-iors of binary powder mixtures, which helps to systematically describe data and facilitate communication among scientists. Perhaps it is with this vision that a simple classification was introduced[27]. This classification, although useful, is not ad-equate to describe diverse types of tabletability observed so far or those that can possibly occur. In this report, a more com-prehensive tableting classification system (TCS) for binary powder mixtures is proposed based on theoretical consider-ations. Characteristics of each system are described. Examples are given when possible. It is hoped that a refined TCS will serve as an initial step toward a more fundamental understanding of powder interactions during compaction. The adoption of TCS is expected to expedite the development of in-depth under-standing of powder compaction of mixtures.

2.

Classification system

The classification of tableting behaviors of powder mixtures is based on tensile strength of tablet compressed under a

constant compaction pressure. For practical reasons, tensile strength is plotted against weight fraction only (alternatives are volume fraction and molar fraction). When tensile strengths of two powders, A and B, are different, A is always used to rep-resent the powder with a lower tensile strength. The weight fraction axis is always expressed as amount of the powder ex-hibiting higher tensile strength. It is possible that under different compaction pressures, the same mixture system may behave differently and fall into a different class because tablet tensile strength depends on pressure differently for different powders. 2.1. Type I

Type I behavior is exhibited if tensile strengths of tablets from individual components are non-zero and if they differ signifi-cantly (>10%) (Fig. 1). Tableting behavior of binary mixture of most fillers and binders exhibit Type I behavior. Type I behav-ior may be further divided into seven sub-classes based on the interaction between the two components.

Type I(a) exhibits ideal behavior, where tablet tensile strength depends on the weight fraction linearly. A straight line may be drawn between points A and B inFig. 1. Both Type I(b) and I(c) exhibit positive deviations from the ideal line. Type I(b) is assigned when tensile strength of tablets of mixtures does not exceed that of B. Otherwise, Type I(c) is assigned. In other words, Type I(c) shows positive deviation so much that some of the mixtures exhibit tablet tensile strength higher than both con-stituent powders. Similarly, Type I(d) is assigned when tensile strength of mixtures negatively deviates from the ideal line but always lies between those of A and B, and Type I(e) is as-signed to systems where negative deviations lead to tensile strength lower than that of A.

Types I(f) and I(g) are characterized by a constant tablet tensile strength (at either low or high end of the curve) over a certain weight fraction of the mixtures (Fig. 1). Outside of this range, tablet tensile strength depends on composition of mixtures. Type I(f) is identified when the flat part of the plot falls in the region where powder B is a minor component (weight frac-tion<0.5). Type I(g) is when the flat part of the plot falls in the region where powder A is a minor component on a weight basis. Depending on the shape of the changing part of the plot, more

Type I 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 w eight fraction Te ns ile s tr ength (M P a)

A

B

A

B

Fig. 1 – Type I behavior of binary powder mixtures: (a) ideal; (b) mild positive deviations from ideality; (c) severe deviations from ideality; (d) mild negative deviations from ideality; (e) severe negative deviations from ideality; (f) tensile strength increases with increasing powder B in mixtures up to a critical composition and subsequently leveled off; (g) tensile strength remains constant up to a critical composition and subsequently increases.

sub-classes may be named. However, further division is re-frained because the feature of the plateau in I(f) and I(g) is already rare. If required in the future, more sub-classes can be introduced as needed.

2.2. Type II

Type II behaviors are special cases of Type I, where tensile strengths of A and B are approximately the same (less than 10% difference) (Fig. 2). Since the tensile strength is identical at the same compaction pressure, the occurrence of type II be-haviors indicates that tabletability curves of two pure powders cross over at the pressure under consideration. Type II powders may be further divided into three sub-categories.

Type II(a) is the ideal case where no interaction between powders A and B is present in the mixtures. Type II(b) behavior deviates from the ideal line positively, i.e., tablet tensile strength

of mixtures is always higher than that of pure powders. Type II(c) behavior negatively deviates from the ideal line, i.e., tablet tensile strength of mixtures is always lower than that of pure powders.

2.3. Type III

Type III is characterized by zero bonding propensity of powder A and mixtures containing A up to a critical concentration (Fig. 3). Sand, glass beads, and rubber particles are examples of the non-bonding powder A, where A–A non-bonding is negligible. The critical point, corresponding to the mixture capable of forming intact tablets, is explained by the percolation theory[10,28–30], above which a continuous matrix of bonding network (A–B and B–B) exists. The mass based critical threshold is likely related to par-ticle size since smaller parpar-ticles can be distributed more uniformly in the mixture and interact with particles of the other mixture component because of their larger surface area. Mix-tures between magnesium stearate and certain tablet excipients may behave in this fashion. Five sub-classes may be identified. Type III(a) exhibits an ideal linear behavior between the criti-cal point and pure powder B. Type III(b) and III(c) exhibit positive and negative deviations from the ideal line. This type of system is relevant to developing compressible tablet formulation of poorly compressible drugs, e.g., acetaminophen. Type III(d) be-havior is identified if the tensile strength of some of the mixtures exceeds that of pure B. Type III(e) is a special case of Type I(f), where component A does not form an intact tablet under the given pressure and adding A to B does not significantly dete-riorate tensile strength of B until a critical amount is reached.

3.

Discussion

The classification system can be useful in developing a better understanding of powder interactions in mixtures. Similar to a mixture of liquids, most mixtures of solids are non-ideal systems. In this case, non-linear relationship between tableting Fig. 2 – Type II behavior of binary powder mixtures:

(a) ideal; (b) positive deviations from ideality; (c) negative deviations from ideality.

Type III 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 w eight fraction T en sile st re n g th ( M P a) a b c

A

B

d

B

A

e

Fig. 3 – Type III behavior of binary powder mixtures: (a) ideal behavior above the critical composition; (b) positive deviations from ideality above the critical composition but tensile strength of the mixture is below that of pure B; (c) negative

deviations from ideality above the critical composition; (d) positive deviation with the maximum tensile strength above that of the pure B; (e) positive deviation with a plateau in the B rich region.

properties, e.g., tensile strength at a given pressure, and composition of powder mixtures may often be observed. Analo-gous to the thermodynamic treatment of non-ideal behavior in mixture systems, a tableting coefficient (TC) may be defined as the ratio of tablet tensile strength that is experimentally ob-served to that as predicted based on ideal linear behavior. Knowledge of TC is useful for the reliable and accurate predic-tions of compaction behaviors of powder mixtures.The TC may be subsequently correlated with physical properties of indi-vidual powder, e.g., particle morphology, particle size, crystallinity, surface roughness, crystal structure, plasticity, brittleness, in-herent bonding strength, and moisture content, for more fundamental studies of interactions between powders. For example, close to ideal mixing behavior may be more likely ob-served when mechanical properties are comparable between the two components in a mixture, while deviations from ideality likely occur when mechanical properties are very different. Clearly, process variables that can influence tablet tensile strength, such as pressure and tableting speed, likely also influence TC. To in-vestigate TC in more depth, a large body of data systematically organized according to the proposed TCS is essential.

Among the main classes of tableting behaviors of mixtures, Type I is more frequently observed in the author’s experience. For example, Type I(a) ideal behavior in theL-lysine

hydrochlo-ride anhydrate and monohydrate system is observed (Fig. 4a). Similarly, ideal mixing behavior is observed between some lactose monohydrate and anhydrate[8,13]. The theophylline monohy-drate and anhymonohy-drate system exhibits Type I(c) behavior (Fig. 4b). In all these systems, particle size and shape between the anhydrate and hydrate crystals are similar. Type I(d) behaviors are observed in mixtures between coarse and fine lactose mono-hydrate[7], and spray-dried lactose monohydrate and micro-crystalline cellulose system (Fig. 4c).Type I(e) behavior is observed in the mixture system of sodium chloride and pregelatinized starch (Fig. 4d)[31]. Type I(g) behavior is observed in the sulfa-merazine polymorphs I and II mixture system (Fig. 4e)[2].

In the TCS, effects of different porosity among tablets of dif-ferent mixtures do not need to be considered to classify tableting behaviors. However, without the knowledge of porosity, con-tributions from both bonding strength and bonding area to tablet mechanical strength must be simultaneously considered, thus making it difficult to interpret data and pinpoint the cause of certain compaction behavior of a mixture.The issue can be par-tially addressed by also calculating porosity of each tablet studied and monitoring change in tablet porosity with composition [23,24,31]. Qualitatively, bonding area is lower at lower poros-ity for similar powders. If multiple data points of tensile strength vs. porosity are available for mixtures, it is beneficial to predict tensile strength of mixtures at zero porosity, which can be used as a measure of bonding strength, by fitting the points to Ryshkewitch equation[32]. In this exercise, it is important to note that the accuracy of data fitting is sensitive to inaccuracy in powder true density that is used to calculate tablet porosity [33,34], and goodness of fitting should be checked visually to ensure global minimum of the residual is attained[35]. It should also be noted that helium pycnometry is not suitable for mea-suring true density of water-containing powders, e.g., polymeric excipients, hydrates, and many amorphous solids[36]. When true density of these powders is needed, an alternative data fitting method can be used[34,36,37].

Three types of interaction, A–A, B–B, and A–B, may be ex-pected in a binary mixture. An in-depth understanding of contributions by each type of interaction is extremely diffi-cult. However, Type III systems may provide opportunities for mechanistic studies of compaction properties of powder mix-tures because the system is greatly simplified by ignoring the A–A interaction.

The type of interaction may change under different com-paction pressures for the same mixture systems. Therefore, if possible, interactions between two powders should be investi-gated under multiple pressures for more insights[30]. In practice, studies carried out at low (e.g., 50 MPa), medium (200 MPa), and high (350 MPa) pressures may suffice. To further simplify it, a commonly accepted pressure relevant to tablet manufactur-ing can be employed for classification purpose. In that case, the pressure of 200 MPa is a good choice. Compaction properties of a granulated binary mixture may be very different from those of corresponding simple blend. It is of value to understand how the processing, such as wet granulation, affects TC and type of behavior in the proposed classification framework. Conceiv-ably, powder interactions may be different at different compaction speed. Thus, the conditions under which the study is performed must be clearly described to avoid confusion. It is important to also note that tablet strength should be quan-tified by tensile strength instead of crushing strength (or its equivalent). The latter is affected by the tablet size and thick-ness while the former is not. In a study of tableting behaviors of mixtures betweenβ-lactose and cellulose, changes in tablet crushing strength is accompanied by changes in tablet thick-ness under an identical pressure[38]. An accurate assignment of tabletability behavior according to this TCS is then not pos-sible based on such data.

Once the interactions for binary mixtures are understood, reliable predictions of powder compaction of binary mix-tures can follow. Subsequently, we can predict the compaction properties of more complex powder mixtures. For example, a mixture of A, B, C, and D may be treated as a binary mixture of A+ B and C + D or any other combinations assuming uniform distribution of components. With a clear understanding of powder–powder interactions in binary and more complex systems, one can efficiently develop a robust formulation based on the knowledge of material properties of a new API as long as a database for various excipients and placebo mixtures is available. The performance of the predicted formulation is then verified with a small number of experiments. As a result, the material and resource required to deliver a robust and high per-formance formulation can be substantially reduced. This is the true spirit of quality-by-design.

4.

Conclusion

A classification scheme for tableting behaviors of binary powder mixtures is described based on theoretical considerations. The consistent use of this system is expected to facilitate the further development of understanding tableting behaviors of binary mixtures, which can be used to guide efficient tablet formulation development based on mechanical properties of APIs and excipients.

Fig. 4 – Examples of tableting behaviors of mixtures: (a) Type I(a),L-lysine monohydrochloride anhydrate and dihydrate mixtures (this work, 160 MPa); (b) Type I(c), theophylline anhydrate and monohydrate mixtures (this work, 100 MPa); (c) Type I(d), spray-dried lactose monohydrate and microcrystalline cellulose mixtures (this work, 150 MPa); (d) Type I(e), pregelatinized starch and sodium chloride mixtures[31]; (e) Type I(g), sulfamerazine (SMZ) polymorphs I and II mixtures[2]. Points in each curve correspond to tablet tensile strength of different mixtures compressed under a constant pressure.

Acknowledgement

I thank PhRMA Foundation for a Sabbatical Fellowship in Phar-maceutics (2014–2015), which facilitated the completion of this manuscript.

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