Harnessing ordered mixing to enable direct-compression process for low-dose tablet manufacturing at production scale

Powder Technology 239 (2013) 290–299

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Harnessing ordered mixing to enable direct-compression process for low-dose tablet manufacturing at production scale Chen Mao ⁎, Venkat R. Thalladi, Derrick K. Kim, Sarina H. Ma, David Edgren, Sami Karaborni XenoPort, Inc., 3410 Central Expressway, Santa Clara, CA 95051, USA

a r t i c l e

i n f o

Article history: Received 12 June 2012 Received in revised form 8 February 2013 Accepted 9 February 2013 Available online 16 February 2013 Keywords: Ordered mixing Content uniformity Direct compression Segregation Quality-by-Design

a b s t r a c t This study demonstrates that the simple direct-compression process can be enabled for low-dose tablet manufacturing through the preparation of an optimal ordered mixture. By producing low-dose tablets containing a micron-sized active pharmaceutical ingredient (API), we showed that excellent content uniformity of a drug product can be accomplished through direct compression, when ordered mixing was introduced as part of the manufacturing process. To incorporate content uniformity into the final drug product, we systematically investigated the material attributes of API and excipients leading to the optimal ordered units. We discovered that excipients with round morphology and rugged surface, which enabled “depth-filling” pattern and multi-layer coverage of API on carrier particles, can give rise to ordered mixtures with greater carrier capacity, stronger adhesive forces, and reduced ordered unit segregation tendency. We developed a sample-saving, bench-scale diagnostic tool which can successfully evaluate the sifting-driven segregation tendency of powder blends. We further identified the conical screen milling process as a robust approach to produce stable ordered mixtures, due to the physical impact and mixing behavior involved in the milling process. This systematic approach, developed on the basis of mechanistic understanding of the critical material and process attributes for ordered mixing and segregation, allowed us to consistently manufacture tablets with high content uniformity both at 1-kg scale and 40-kg scale. Through this study, we demonstrated that common risks associated with the direct-compression process at production scale, such as content uniformity, can be mitigated by understanding and manipulating the particle–particle structures and interactions of the formulation components. © 2013 Elsevier B.V. All rights reserved.

1. Introduction Content uniformity, among basic requirements for the manufacturing of solid dosage units, is a particularly important attribute for drug products containing low levels of active pharmaceutical ingredients (API) [1]. For low-dose solid dosage forms, consistently meeting the content uniformity criteria at production scale is a challenging task. Failing to meet content uniformity can lead to sub-potency or superpotency of drug products, which remains to be a common cause for drug product recalls today. To produce solid dosage forms (such as tablets or capsules) with acceptable content uniformity, it is critical to prepare a powder blend which not only contains uniformly mixed API, but also defies segregation in downstream processes [2]. Therefore, granulation is usually the first choice for preparation of homogeneous, segregation-resistant blends because of the strong API-excipient bonds formed by the agglomeration process. Although a homogeneous blend is usually attainable, the challenge of obtaining a segregation-resistant blend precludes the widespread use of the simpler direct-compression (DC)

⁎ Corresponding author. Tel.: +1 408 616 7276. E-mail address: [email protected] (C. Mao). 0032-5910/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.powtec.2013.02.016

process, which would otherwise be desirable for manufacture of low-dose drugs [3,4]. The introduction of the “ordered mixing” concept in the 1970s [5–7] allows for the possible production of low-dose formulations through dry mixing, hence the DC process. Ordered mixing is achieved by adherence of fine API particles to the surface of coarser excipient carriers to form “ordered units” [8]. A perfectly ordered mixture exhibits a high degree of homogeneity comparable to completely randomized mixtures [9,10]. The variation of API content in an ordered mixture was theoretically and experimentally shown to be less dependent on sample size [10–12]. More importantly, if the interactions between the API and carrier particle are strong, and the ordered units do not segregate, a stable segregation-resistant mixture can be made [13–16]. Several authors reported that low-dose tablets produced by direct compression of ordered mixtures at lab scale exhibited excellent content uniformity and were free from segregation [13,17–19]. To empower the DC process for low-dose tablet manufacturing, ordered mixing is the central operation to ensure good content uniformity at production scale. Practically, a uniform API distribution should not only be achieved immediately following blending, but also maintained at the final tabletting or capsule filling stage. Thus, one is required to incorporate multiple quality attributes into the

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ordered mixture. Aside from a uniform distribution of API within the mixture, the available adherence sites in carriers and the strength of the API-carrier interactions should be adequate to prevent “constituent segregation” [8,20,21], which can occur when excess or dislodged API segregates during the downstream processes. Furthermore, commercial excipients are not uniformly sized. The API content in individual “ordered units” of different sizes can be different [22], and it can give rise to “ordered unit segregation” in subsequent handling [8,20]. Taken together, there are multiple quality attributes of an ordered mixture to enable a DC process for low-dose drugs; these attributes include API blend homogeneity, minimal free API within mixture, strong API-carrier adherence, and small variation of API content in individual ordered units. The incorporation of these attributes into an ordered mixture requires a great level of scrutiny from both material and processing perspectives. There are a large variety of potential excipients and mixing operations available for this purpose. The development of such mixtures can comprise multiple steps, which can include modifying API particles and selecting carrier excipients to achieve the desired mechanism of spontaneous adhesion, designing an appropriate mixing process to facilitate the formation of ordered mixture, and assessing the propensity of segregation of resulting mixture. In this paper, we depict a systematic approach for ordered mixing development at bench scale, which encompasses the considerations of materials, process development, and segregation diagnosis. Our goal is to design content uniformity into a DC-based manufacturing process through manipulating ordered mixing, so that dose uniformity is accomplished regardless of production scale. There have been discussions regarding the circumstances under which the phrase “ordered mixture” should be used [23]. It was proposed to use the degree of mixture homogeneity as the criterion. Mixtures similar to what is described in this paper were sometimes called “pseudorandom mixture” or “interactive mixture”, because random processes still take place within them [24–26]. The adoption of these names has not been harmonized in literature. In this work, we chose to use the phase “ordered mixture” in accordance with the original concept of ordered mixing: order is intentionally introduced to a historically disordering (mixing) process [5].

2.3. Primary characterization of excipients

2. Materials and methods

2.6. Tablet manufacture

2.1. Materials

At bench scale, tablets with approximately 5% API (by weight) were manufactured at 1-kg scale using a DC method. To optimize blend homogeneity, a multi-step blending process was employed. The powder of API, or an ordered mixture of API and carrier particles, was sandwiched between pre-mixed excipients. The ordered mixture preparation for tablet manufacture is discussed in Section 3.5. The entire powder mixture was then blended in a V-blender for 10 min. Magnesium stearate was added last and the mixture was further blended for 4 min. Tablets from the final blends were compressed using an instrumented rotary tablet press. The compression force was optimized to give desired tablet thickness and tensile strength. The API content uniformity was assessed from 7 to 8 sample sets (3 tablets per sample) that evenly spanned the course of the tablet compression. At production, the manufacturing operation was carried out at approximately 40-kg scale. The initial step included the preparation of an ordered mixture of API and the carrier excipient. The mixture was layered in between other excipients for further mixing and lubrication. The final blend was carefully transferred to the hopper of a rotary tablet press. The compression pressure settings were adjusted to match the tablet thickness and tensile strength obtained at the bench scale development. 11 sample sets (6 tablets per sample) that evenly spanned the duration of the compression run were collected to determine the API content uniformity.

The API in the form of a crystalline solid was supplied internally. Calcium phosphate dihydrate (Di-Tab) was supplied by Innophos (Cranbury, NJ, USA). Microcrystalline cellulose (Avicel PH200) was received from FMC (New Brunswick, NJ, USA). Pregelatinized starch (C*PharmGel 12012) was supplied by Cargill (Cedar Rapids, IA, USA). All excipients used were of USP grade.

2.2. Primary characterization of API The particle size distribution of the API was determined using an image-based Sympatec QicPic particle size analyzer (Clausthal– Zellerfeld, Germany). This analyzer was equipped with a RODOS dispersion module and VIBRI OASIS/L feeder. Approximately 800 mg of powder sample was fed into the measuring compartment at a vibratory feed rate of 20%. The dispersion pressures were varied from 0.1 to 1.0 bar; the images of particles were captured using an M6 lens (measuring range 5–1705 μm) at a rate of 450 Hz. The morphological characteristics of the API were obtained using a Hitachi S-3400 scanning electron microscope (SEM) (Pleasanton, CA, USA). Powder solids were mounted on a double-sided carbon tape. SEM images were captured using secondary electron detection.

The particle size distribution and morphological characteristics of excipients were obtained using the methods described in Section 2.2. The specific surface area of excipients was determined from the Brunauer–Emmett–Teller (BET) analysis of adsorption isotherms using a Micromeritics Gemini V surface area analyzer (Norcross, GA, USA). Nitrogen was used as adsorbing gas at five partial pressures ranging from 0.05 to 0.25. Samples were out-gassed in vacuum at room temperature overnight prior to measurements. 2.4. Preparation and characterization of binary ordered mixtures Prior to mixing, the API powder was screened through 45-μm screen. The size fraction of the excipients between 180 and 250 μm was individually mixed with the screened API in the ratio of 10:1 (by weight) in a Turbula mixer (Glen Mills, Clifton, NJ, USA) for 20 min. The mixtures were then subjected to sonic sifting using a GA-6 Gilsonic Autosiever (Lewis Center, OH, USA) on a 180-μm screen to allow passage of free or detached API particles. The content and standard deviation of the adhering API on the ordered units were determined through HPLC analysis in triplicate. The morphology and surface features of the ordered units were obtained by SEM analysis. The strength of the API-carrier interactions was evaluated by sonic sifting of mixtures on a 180-μm screen at equivalent vibration conditions (amplitude 20 plus vertical tapping). API detached from the carrier fell through the screen, resulting in lower API concentration in mixtures. Multiple 500-mg samples were taken from mixtures prior to, and after, 5, 10 and 15 min of vibration. The API concentrations of the samples were obtained through HPLC analysis. 2.5. Assessment of ordered unit segregation of binary ordered mixtures Ordered mixtures were prepared by mixing unclassified excipients with screened API in the ratio of 20:1 (by weight) in a Turbula mixer for 20 min. The resulting mixtures were then sieved through a stack of screens of 425, 250, 180, 150, 106, and 75 μm in size. The powder retained on each screen was collected and analyzed using HPLC to measure the API content on carriers in each particle size range.

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2.7. Evaluation of sifting-driven segregation tendency The sifting-driven segregation tendency assessment was implemented on samples immediately after the final blending step, before blends were set to receive further handling that may trigger segregation. A powder blend of 5 g was loaded onto the top of a sieve stack comprised of 6 sieves (425, 250, 180, 150, 106, and 45 μm) and a bottom fine collector. The choice of sieve sizes was shown to have minimal effect as long as an adequate number of sieve fractions encompassing the entire blend particle size distribution were employed. The sieve stack assembly was secured to the sonic siever and subjected to oscillation (amplitude 20) and vertical tapping for a period of 4 min, a condition leading to complete separation of powder based on their particle sizes. For each blend, a segregation index (SI) value was calculated from the blend distribution and the API distribution within the blend after sieving. The derivation and experimental verification of the SI index are given in Appendix A. 2.8. Evaluation of fluidization segregation tendency The fluidization segregation tendency of blend was assessed using a fluidization segregation tester (Jenike & Johanson, Tyngsboro, MA, USA) conforming to the ASTM D6941-05 standard [27]. 75 mL of the blend was charged into the testing chamber. A pre-determined fluidization profile was employed to bring the powder to a completely fluidized state, followed by slow settlement. After the blend settled, three samples were each taken from the top, center and bottom cylinders and the API contents were measured using HPLC analysis. 3. Results and discussion 3.1. Morphological characteristics of API and carriers favoring ordered mixing The particle size distribution and SEM micrographs of the API are shown in Figs. 1 and 2, respectively. The d10, d50, and d90 values of the primary particles, obtained from a wet dispersion method, were 0.7 μm, 2.1 μm, and 8.3 μm, respectively. Due to their micrometer sizes, the particles exhibited strong tendency to form agglomerates of a broad size distribution. Additionally, higher velocity of the dispersion air could not completely break the association between individual particles (Fig. 1), indicating strong API cohesion. The small size and strong cohesion of API particles are believed to favor the formation of stable ordered mixtures, provided that a desirable carrier can be selected. Three common diluent excipients, calcium phosphate dihydrate (DiCal), microcrystalline cellulose (MCC), and pregelatinized starch 1

density distribution (q3)

0.9

0.1 bar 1.0 bar

0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 1

10

100

1000

10000

particle size (µm) Fig. 1. Particle size distribution of the API obtained from an image-based particle size analyzer at different air dispersion pressures.

were studied as potential carriers for ordered mixtures. All excipients had similar particle size distribution with volume median diameter between 200 and 250 μm. As shown in Fig. 3, The excipient particles either possessed highly textured surfaces [28,29], such as DiCal and MCC, or were macroporous [30,31], such as starch. Both features are believed to favor stable ordered mixtures with a high capacity to host API [32]. Excipients with smooth surfaces were not used. The morphological characteristics of the excipients after mixing with API (in 10:1 ratio by weight) are shown in Fig. 3. All three excipients demonstrated “furry” appearance as previously reported in other systems [13]. At this API proportion, the patterns of API-carrier interactions exceeded partial coverage [22] or even coating [9,20] on carrier particles, which was observed for mixtures of low drug content (usually below 1% by weight). Instead, the fine API particulates appeared to cover almost all the open and deep valleys on the surfaces, resulting in a dramatically reduced rugosity of the carrier particles (Fig. 3). For the angular, highly porous starch particles, mixing with API enabled all the pores and grooves to be filled. The multi-layer, pore-filling coverage pattern was expected to produce stable ordered mixtures with higher drug load. 3.2. Carrier capacity and API-carrier adhesion strength Individual carrier particles can carry finite amount of API particulates. When carrier capacity is exceeded, excess API particles are present in either a free or self-agglomerated form, separate from the ordered units [33,34]. Under these circumstances, moderately increasing drug load was seen to reduce blend homogeneity and aggravate segregation [15,35], opposite to random mixtures where high drug load usually led to greater homogeneity. It is therefore ideal to evaluate the capacity of the carrier excipient and keep its proportion above a certain level to prevent over-saturation of carriers by the API. The capacities of excipients (between 180 and 250 μm) to host the API are provided in Table 1. Recall that the initial blends were mixed at 10:1 (excipient:API) ratio (see Section 2.4). The lower API content in the final ordered mixtures indicated that significant amount of original API was free after mixing and was removed by sifting [7]. All three excipients studied were highly textured or porous and were therefore capable of hosting significant amount of API (between 4.2 and 6%). The excipients used were classified and had similar particle size and size distribution, but different morphology, density, and surface roughness. The DiCal surface has deeper, more rugged texture, which allowed the carrier to host similar weight percentage of API as MCC (Fig. 3), despite its much higher density (Table 1). The highly porous structure and low bulk density enabled starch particles to host a greater amount of API. Because of the observed multilayer coverage and pore-filling patterns, and because excipients may have capillary pores inaccessible by API particles, neither the particle size [8,22], nor the specific surface area [7] was indicative of the capacity and quality of the carrier excipients (Table 1). It has been shown that the API-carrier adhesion strength was directly related to blend segregation if subsequent handling involved mobilization of powder, such as vibration or fluidization [11,36,37]. Selecting a carrier that engages in strong API-carrier adhesion is thus desirable toward the production of a segregation-resistant blend. The inter-particulate forces are a subject of active research in pharmaceutical powders, especially in conjunction with dry powder inhaler (DPI) formulations [38,39]. The common inter-particulate interactions usually include van der Waals forces [40], tribo-electric forces [41,42], capillary forces [43], and mechanical interlocking [29]. For micron-sized particles similar to the API used in this work, van der Waals forces are frequently the dominant type of interaction [40]. The electrostatic charging generated during powder processing is also a common cause for particle–particle adhesion [44,45]. Although the dominant types of API-carrier interaction were unclear, our API exhibited an inherent affinity to all the carriers we chose.

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Fig. 2. Scanning electron micrographs of API showing the agglomeration of primary particles.

A1

A2

B1

B2

C1

C2

Fig. 3. Scanning electron micrographs of excipients before (1) and after (2) mixing with fine API particulates. A: DiCal; B: MCC; C: Pregelatinized starch.

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Table 1 The bulk density, mean particle size, and specific surface area of the excipients (between 180 and 250 μm) used for ordered mixing, and the capacities of excipients to host the API after the ordered mixtures were produced. Excipient

Bulk density (g/cm3)

Mean particle size (μm)

Specific surface area (m2/g)

Weight of API per unit weight of excipient (%)

DiCal MCC Starch

0.78 0.33 0.26

237 244 261

1.93 1.00 0.15

4.2 ± 0.00 4.5 ± 0.04 6.0 ± 0.20

Based on this observation, we were interested in evaluating the strength of API-carrier adhesion of the ordered mixtures, particularly as the function of carrier morphology and surface structure. The strength of API-carrier adhesion was evaluated by subjecting ordered mixtures to vibration for a fixed period of time. The ability of API-carrier affinity to withstand vibrations is shown in Fig. 4. For all systems tested, over 80% of the API remained attached after 15 min of vibration, which indicated that the API-carrier adhesion strength was sufficiently strong to withstand powder mobilization expected during normal handling. The loss of API was initially fast, but tapered off after 5 min of vibration, reflecting a distribution of inter-particle forces. The API–starch system appeared to lose more API, compared to DiCal and MCC systems, and exhibited higher variability. This observation agreed with the morphological characteristics of starch particles, which had smoother surface than DiCal and MCC. It was repeatedly shown that smooth-surfaced particles carried less API and produced less stable ordered units [6,29,31]. While the highly porous structure of starch resulted in a high hosting capacity by allowing API particulates to fill holes and grooves, the smoother surface was detrimental to the physical stability of the resulting ordered mixture. 3.3. Uniformity of ordered units At low drug levels, API was shown to distribute in a manner that was proportional to the specific surface area of the carriers. i.e. the API weight per unit surface area of carrier remained approximately constant [8,46]. Large carrier particles, having smaller specific surface area, were expected to carry a lower proportion of API. The API segregation could ensue if ordered units of different sizes segregate from one another. Ideally, this type of segregation can be eliminated by controlling carrier particle size in a narrow range; nevertheless, this is largely impractical for commercial drug manufacturing. It is therefore necessary to identify, whenever possible, an excipient which is less susceptible to ordered unit segregation. 105

API-DiCal API-MCC API-Starch

% API retained

100 95 90 85 80 75 70 0

2

4

6

8

10

12

14

16

vibration time (minutes) Fig. 4. Loss of API from carrier particles (180–250 μm) as a function of vibration time under sonic sifting.

The ordered unit uniformity was assessed by preparing ordered mixtures using unclassified excipients, and assessing the drug content of the ordered units of different size fractions separated by sieving (see Section 2.5). In Fig. 5(A–C), the API concentrations in ordered units of a wide particle size range are presented. In all tested systems, the variations of API concentration among different size fractions were significantly lower than the theoretical calculations assuming constancy of API per unit surface area, calculated from the projected carrier particle size (Fig. 5D). We believe the observed improvement of uniformity of the ordered units was due to the specific “depth filling” patterns of the API–carrier interactions. The surface area-controlled drug distribution took place when two conditions were met: 1) a constant percentage of surface coverage of API on carriers, and 2) a monolayer or constant thickness of API layer at the coverage sites [12]. These conditions have been observed experimentally at very low drug content for smooth-surfaced carriers [22]. At higher drug content and for highly textured carriers, as in our studies, these conditions did not hold. Our experimental results suggested that, for ordered mixture preparation, the “depth filling” mode may be more desirable than “surface coating” for the purpose of reducing ordered unit segregation. Due to its high capacity, strong affinity to API, enhanced ordered unit uniformity, and high density, DiCal was used as the carrier excipient for the subsequent studies on ordered mixing processes and tablets preparation. 3.4. Characterization of blends and tablets without ordered mixing Prior to evaluating different mixing processes, a control blend was prepared by mixing all formulation components (including API and DiCal) through conventional V-blending, followed by lubrication (see Section 2.6). The sifting-driven segregation tendency of blends was assessed using a sieving-based method (see Section 2.7 and Appendix A). A segregation index (SI) was derived from the sieve data, and was experimentally verified (see Appendix A). A high SI value indicates greater sifting-driven segregation tendency of a blend. As shown in Fig. 6, the sieve analysis of the control blend gave rise to highly API-rich powder on the larger screens. The powder retained on the 425-μm screen contained 46% of API (in contrast to the label claim of approximately 5%). Although the weight of the powder retained on the screen only accounted for 2.6% of the total blend (see Fig. 7), the high proportion of API retained on the coarser particle size screens caused the finer part of the blend to fall below the label claim. This sifting pattern forecasted that the poor content uniformity of tablets will result from small, API-deprived particles sifting toward the bottom of the hopper when the powder bed is disrupted due to, for example, the mechanical vibration during tabletting. The SI value obtained from the blend was 0.70, which corresponded to a low similarity between the size distribution of the API and the whole blend (Fig. 7), and hence a high risk for sifting-driven segregation. The maximum SI for 5% API load is 1.9, corresponding to the scenario where the API and rest of the blend are completely separated after sieving. The diagnosed high segregation tendency and segregation pattern agreed well with the results from the tablet compression study. The content uniformity of the control blend during the course of the tablet compression is shown in Fig. 8A. As the compression progressed, there was an upward trend of the tablet potency, reflecting an axial API concentration gradient in the hopper. The tablet-to-tablet variations at individual time points were also high. The relative standard deviation (% RSD) was 6.3%. To confirm that the poor content uniformity of the non-ordered mixing blend arose from sifting-driven segregation rather than fluidization-driven segregation, we evaluated the fluidization segregation tendency of the powder blend (see Section 2.8). The level of fluidization segregation was minor and the pattern was opposite to the tablet content uniformity studies (data not shown). We therefore

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5

5

API weight percentage

A: DiCal

B: MCC

4

4

3

3

2

2

1

1

0

0 75-106

106-150

150-180

180-250

250-425

>425

75-106

106-150

180-250

250-425

>425

5

5

C: Starch API weight percentage

150-180

D: Specific surface area-controlled

4

4

3

3

2

2

1

1

0

0 75-106

106-150

150-180

180-250

250-425

>425

75-106

106-150

partice size (µm)

150-180

180-250

250-425

>425

partice size (µm)

Fig. 5. The API concentrations of ordered units in different size fractions for ordered mixtures containing DiCal (A), MCC (B) or Starch (C). Fig. 5D was calculated based on the assumption of constancy of API per unit surface area of carriers.

concluded that sifting was the dominant factor for powder segregation and the undesirable content uniformity. The studies suggested that, although DiCal has been shown to be an excellent carrier for the API, conventional V-blending was not capable of producing quality ordered mixture; the blend possessed intrinsically high segregation tendency. 3.5. Optimization of ordered mixing process Using a conventional V-blending procedure, we showed that the API was present as agglomerates and a quality ordered mixture cannot be obtained. An improved mixing process was then investigated. The formation of an ordered mixture was proposed to be a two-stage

process, which consists of an API de-agglomeration stage, followed by an adhering stage [14]. A desired mixing process should therefore possess following two elements: 1. Breaking and dispersing the API agglomerates; and 2. Providing intimate contact between the API and the carrier particles. Early literature suggested to increase the rate of energy input as an approach to improve ordered mixing [14]. It was also reported that vigorous convective or “frictional” (shear) mixing with coarse carrier particles can efficiently break agglomerates and form ordered mixtures [5,20]. To incorporate these mixing elements into scalable manufacturing, we chose conical screen milling (comilling) as the process to produce ordered mixtures. Comilling was recently reported to improve 0.35

0.5

API whole blend

0.3

weight fraction

API weight fraction

0.4

0.3

0.2

0.1

0.25 0.2 0.15 0.1 0.05 0

0 <45

45-75

75-106 106-150 150-250 250-425

>425

size fractions (µm) Fig. 6. The API content in each sieve fraction after the control blend, prepared by conventional V-blending, was sieved.

<45

45-75

75-106 106-150 150-250 250-425

>425

size fractions (µm) Fig. 7. Size distribution of API within the blend and of the whole blend prepared by conventional V-blending.

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C. Mao et al. / Powder Technology 239 (2013) 290–299 Table 2 SI values of the powder blends obtained from conical screen milling of the API and DiCal particles using different screen sizes, and the content uniformity, in % RSD of the API content, of the corresponding tablets.

A % label claim

110

100

Screen diameter (μm)

SI

% RSD

No milling (V-blending) 1397 813 457

0.70 0.34 0.14 0.06

6.34 2.92 2.66 1.00

90

content uniformity of the corresponding tablets (Fig. 8A, B). Furthermore, Table 2 showed that segregation tendency of the mixture can be reduced by comilling with smaller screens. By reducing the conical screen size, we observed a strong and consistent improvement on de-agglomeration and subsequently the equalization of API concentration throughout all the carrier size fractions (Fig. 9). The choice of conical screen size had limited effect on the particle size distribution of the final blend (Fig. 10). Therefore, the observed equalization of the API concentration should predominantly result from the stronger powder impact and more vigorous mixing within the conical mill, which was achieved by longer residence time using smaller screens.

B % label claim

110

100

90

3.6. Ordered mixing improves content uniformity at production-scale manufacture

% label claim

110

100

90

10

25

40

55

70

85

100

% run time Fig. 8. Content uniformity of the powder blends during the course of the tablet compression. A: with conventional V-blending of API and DiCal at 1-kg scale; B: with comilling of API and DiCal using 457-μm round screen at 1-kg scale; C: with comilling of API and DiCal using 813-μm round screen at 40-kg scale.

flow properties of MCC, essentially through the preparation of a colloidal silica–MCC ordered mixtures [47]. We anticipated that the impact between the impeller and the powder that can occur in comilling was sufficient to break apart API agglomerates while at the same time engage shear mixing [48,49]. To increase the mixing efficiency, we chose the screens with round holes and smooth surfaces (type R screens), instead of the grated surfaces (type G screens), because the smooth surface allows powder to reside longer in the mill; grated apertures of the same bore size facilitates the powder to leave the mill faster through the guided channels formed by the grates [49]. We postulated that a long residence time of the powder in the mill was instrumental to achieve thorough impact and mixing. We implemented ordered mixing by comilling the API–DiCal binary system using three type-R screens of different sizes (1397, 813 and 457-μm). The resulting mixtures were further blended with other excipients to produce the final blends for tabletting. The segregation assessment, both in the form of the SI values and the content uniformity of the resulting tablets manufactured at 1-kg scale, were conducted. As shown in Table 2, the introduction of comilling, regardless of screen size, led to markedly improved ordered mixtures compared with the conventional V-blending process. This was demonstrated by the significantly reduced SI values of the blends and improved

At bench scale, we successfully developed an ordered mixing process to achieve excellent content uniformity through direct compression. We believe that the content uniformity could be scaled to larger manufacturing processes as long as all the material and processing attributes for ordered mixing, developed at bench scale, were maintained. To demonstrate this, tablet manufacturing was conducted at approximately 40-kg scale following the identical formulation and process chain (using larger conical screen mill, 813-μm round screen and larger V-blender). The production-scale batch exhibited excellent content uniformity (% RSD = 1.4, see Fig. 8C). The SI values of the blends produced at two different scales were also very similar (0.14 at 1-kg scale versus 0.15 at 40-kg scale). Through successful incorporation of content uniformity in both scales, we demonstrated that risks of poor tablet content uniformity using DC processes can be significantly mitigated by understanding and harnessing the material and process attributes relating to ordered mixing and segregation. These attributes include high carrier capacity to host API, strong API-carrier affinity, relatively constant API proportion on individual carrier particles regardless of their sizes, and achievement of intimate mixing between API and carriers. For a micron-sized, adhesive API like ours, we found that 0.5 no comilling 1397-micron screen 813-micron screen 457-micron screen

0.4

API weight fraction

C

0.3

0.2

0.1

0 <45

45-75

75-106

106-150 150-250 250-425

>425

size fractions (µm) Fig. 9. The API content in each sieve fraction, obtained from the sieve analysis on the final powder blends which included comilling of API and DiCal using screens of different sizes.

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0.35

weight fraction

similarity between these two distributions is expected. This similarity can be achieved when one of the following two conditions is met [51,52]:

no comilling 1397-micron screen 813-micron screen 457-micron screen

0.3 0.25

1. API has the same size distribution as the entire blend; or 2. API particle differs in size from the rest of the blend, but possess poor flowability, such that movement of an API particle against other particles in the blend cannot be achieved during the mobilization of the powder bed.

0.2 0.15 0.1 0.05 0 <45

45-75

75-106 106-150 150-250 250-425

297

>425

size fractions (µm) Fig. 10. Particle size distribution of the whole blends, obtained from sieve analysis on the final blends which included comilling of API and DiCal using screens of different sizes.

carriers with round shape and high surface roughness are more favorable to attaining these attributes. For scale-up consideration, we also recommended examining the process conditions for manufacturing at large scale, and developing and applying the segregation diagnostic tools that can simulate such process conditions on powder blends. We believe that the implementation of appropriate diagnostic tools can facilitate the understanding of segregation mechanisms during the development stage, using small quantities of samples, and greatly reduced the risk of segregation at production scale. When such understanding and diagnostic tools are in place, wide adoption of the production-scale DC process for low-lose formulations will become increasingly attractive. 4. Conclusion We have shown that successful development of an ordered mixture enabled the use of direct-compression process to manufacture tablets of low drug load. To produce an optimal ordered mixture, we closely examined the structural aspects of API and carrier particles, and investigated the effect of these aspects on the capacity, physical stability and segregation tendency of the ordered mixtures. We also identified comilling as an effective approach to accomplish the desired APIcarrier ordered units due to the strong physical impact and shear mixing involved in the process. The identification of critical material and process attributes for ordered mixing and segregation allowed us to consistently produce tablets with high content uniformity, regardless of batch scale. This study exemplified, at the particulate level, the connectivity between the materials science tetrahedron (MST) concept [50] and the Quality-by-Design approach in solid-dosage form manufacturing. Namely, quality drug product may be produced by gaining the fundamental understanding of interplays between the structure–property relationships of components and of the processes that harness the relationships. If such understandings are successfully implemented, more effective, science-based, and performance-driven drug development is possible. Appendix A A diagnostic tool for sifting-driven segregation was developed on the basis of a simple sieving method. Sieve analysis results in a histogram representing the particle size distribution of the powder. For a segregation-prone blend, sieving will result in a great disparity between the particle size distribution of the component in question (represented by API in the following texts) and the particle size distribution of the whole blend; for a segregation-resistant blend, a

It is therefore possible to assess the sifting-driven segregation tendency of a powder blend by measuring the level of similarity between these two particle size distributions (distribution of the API in blend, and the whole blend) after a controlled sieve analysis. Given, a total number of I sieve screens (including the bottom fine collector) are employed for the sieve analysis; the weight fraction of the powder blend in each sieve is denoted as wi; and the weight percentage of API in each sieve fraction is pi. The cumulative size distribuwp tion of API and the entire blend can be expressed as: ∑ i i and p i ∑ wi , respectively, where p is the weight percentage of API in the i

whole blend given by p ¼

I X

wi pi . Because sifting-driven segregation

i¼1

tendency is quantified by the extent of similarity between these two distributions, the following segregation index (SI) is proposed from the mean absolute error of two distributions:

SI ¼

   I  I X   X p wi pi −w  ¼ wi  i −1: i  p p i¼1

i¼1

Lower SI value indicates greater similarity between API and blend distributions after sieving, which infers lower sifting-driven segregation tendency. Table A1 Summary of the characteristics of powder blends used for tablet manufacture for the verification of the segregation diagnostic tool. Batch number

Drug load

API primary particle size, d90, (μm)

Blending step

Diluent

Low shear Intermediate shear, short duration Intermediate shear, intermediate duration Intermediate shear, long duration Intermediate shear, intermediate duration High shear Intermediate shear, short duration Intermediate shear, intermediate duration Intermediate shear, intermediate duration Intermediate shear, intermediate duration Intermediate shear, intermediate duration Intermediate shear, intermediate duration Intermediate shear, intermediate duration Intermediate shear, intermediate duration Intermediate shear, intermediate duration

A A

1 2

5% 5%

10 10

3

5%

10

4

5%

10

5

5%

10

6 7

5% 10%

10 10

8

10%

27

9

10%

27

10

10%

27

11

10%

10

12

10%

10

13

10%

42

14

10%

42

15

10%

27

A A B A A C C C C C C C C

298

C. Mao et al. / Powder Technology 239 (2013) 290–299

Fig. A1. Correlations between the SI (solid line) and DP (dashed line) values of the blends and the % RSD of the API content of the resulting tablets.

Multiple DC formulations of the API were used to test the validity and sensitivity of the diagnostic tool. In totality, 15 batches of direct-compressed tablets were produced at 1-kg scale. These batches were manufactured with varying drug loads, API primary particle sizes, blending steps and types of diluent excipients. The attributes of the 15 batches are summarized in Table A1. Verification of the diagnostic tool was conducted by evaluating the correlation between the SI values of the final blends and the content uniformity (reported by relative standard deviation, or % RSD of the drug content corrected for tablet weight) of the tablets compressed from the corresponding final blends. As shown in Fig. A1, we observed a strong correlation (R 2 = 0.89) between the SI values of the blends and the content uniformity of the resulting tablets. This correlation demonstrated that the SI is a good index to diagnose the sifting-driven segregation tendency of a powder blend. The correlation was built upon formulations with different drug loads, material attributes and process parameters, which suggested that the diagnostic tool was robust against changes that routinely took place during a formulation and process development. Because this method evaluates the inherent blend properties, it should be independent of the scale of the manufacturing processes. In addition, the studies were conducted using five grams of powder. This method could therefore enable the segregation tendency analysis with significantly reduced sample requirement as compared to the ASTM standard method [53]. The derived SI equation is conceptually similar to the “demixing potential” (DP) originally developed by Thiel and Nguyen [19,54,55], which is essentially the coefficient of variation of API within the blend. Our verification studies showed that the SI index appeared to establish a stronger correlation than demixing potential in assessing the segregation tendency of our formulations (Fig. A1). References [1] United States Pharmacopeia 34. b905> Uniformity of dosage units, Pharmacopeial Forum 35 (3) (2011) 724. [2] J.C. Samyn, K.S. Murthy, Experiments in powder blending and unblending, Journal of Pharmaceutical Sciences 63 (3) (1974) 370–375. [3] M. Jivraj, L.G. Martini, C.M. Thomson, An overview of the different excipients useful for the direct compression of tablets, Pharmaceutical Science and Technology Today 3 (2) (2000) 58–63. [4] K.A. Khan, C.T. Rhodes, The production of tablets by direct compression, Canadian Journal of Pharmaceutical Sciences 8 (1) (1973) 1–5. [5] J.A. Hersey, Powder mixing by frictional pressure: specific example of use of ordered mixing, Journal of Pharmaceutical Sciences 63 (12) (1974) 1960–1961. [6] J.A. Hersey, Ordered mixing: a new concept in powder mixing practice, Powder Technology 11 (1975) 41–44. [7] D.N. Travers, Some observations on the ordered mixing of micronized sodium bicarbonate with sucrose crystals, Powder Technology 12 (1975) 189–190.

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