Tablet capping predictions of model materials using multivariate approach

International Journal of Pharmaceutics 569 (2019) 118548

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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Tablet capping predictions of model materials using multivariate approach a

a

Pratap Basim , Rahul V. Haware , Rutesh H. Dave a b

a,b,⁎

T

Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY, USA Natoli Institute for Industrial Pharmacy Research and Development, Long Island University, Brooklyn, NY, USA

A R T I C LE I N FO

A B S T R A C T

Keywords: Capping Powder rheology Plastic deformation Elastic deformation Air entrapment Multivariate analysis Powder cohesion

The present study demonstrated the prediction of predominant root causes of capping behavior as a function of the powder rheological and the mechanical behavior of Acetaminophen (APAP) and Ibuprofen (IBU). The authors analyzed powder rheological properties for powder blend permeability, pressure drop, and cohesion. The measured deformation properties were compact porosity, internal air pressure, Brinell hardness, and tensile strength. The data were evaluated qualitatively and quantitatively using multivariate techniques, such as principal component analysis (PCA) and principal component regression (PCR) models, respectively, to identify the effect of powder air entrapment efficiency and mechanical behavior on the tablet capping score. The PCA model indicated that pressure drop, cohesion, API amount, and compression pressure correlated positively, whereas permeability, porosity, internal air pressure, Brinell hardness, and tensile strength correlated negatively to the capping potential. APAP and IBU also showed two independent mechanisms as a function of their amount on the capping score at all compression pressures. APAP and IBU followed an exponential and linear relationship, respectively. Furthermore, the dominant powder rheological and deformation behavior affecting the capping score of each material was identified and quantified using two separate PCR models. These models showed that APAP capping was predominantly dependent on its powder properties, while that of IBU was predominantly based on its deformation properties. In conclusion, APAP and IBU compacts capping had respective air induced and deformation induced capping behavior. The proposed approach can aid in understanding the underlying mechanisms of capping and developing an effective, optimized strategy to ensure tablet quality.

1. Introduction

FDA has stimulated continuous research in this area (Martens and Martens, 2000). However, the development of defect-free smooth tablet production based on a thorough scientific understanding is still far from reality. The success of powder compression into a compact of desired integrity depends on an interplay of powder blend properties and various compression parameters. Thus, it is essential to correlate the physics of powder blend properties and material deformation during compression to establish a “cause and effect” relationship to decode either the failure or success of the compression process. Pharmaceutical powders are heterogeneous and are composed of billions of individual particles having different sizes and shapes that are randomly interspersed with air space (Dudhat et al., 2017; Latchman et al., 1990). The powder flow dictates the amount of void or space between particles before compaction. These spaces are responsible for entrapped air in the powder blend (Tomita, 1994). This entrapped air interferes with the interparticle bonding under the compression pressure, leading to a poor tabletability (Dudhat et al., 2017). Hence, it is essential to understand the ability of the powder bed to relieve the

A tablet manufacturing science is still in the primitive stages as compared to, say, the aviation industry though both started about the same time (Wells, 1993). This science lacks a “general compression equation” to enable the understanding and prediction of the powder compression process that is a key step in the science of tablet manufacturing. Thus, several approaches are combined to understand the mechanisms associated with the tableting process (Haware et al., 2009). A failure to acquire a prior scientific understanding of powder behavior as a response to applied compression conditions can lead to any number of manufacturing problems such as capping, lamination, picking, and sticking. This, in turn, can lead to an entire batch failure, production delays, and time to market. Capping is one of the most common problems faced during pharmaceutical tablet production. It is defined as the separation of the top or bottom layer of the tablet, either partially or completely (Dudhat et al., 2017). A new emphasis on ICH Q8 guidelines provided by the US

⁎

Corresponding author at: Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201, USA. E-mail address: [email protected] (R.H. Dave).

https://doi.org/10.1016/j.ijpharm.2019.118548 Received 9 April 2019; Received in revised form 18 June 2019; Accepted 19 July 2019 Available online 30 July 2019 0378-5173/ © 2019 Elsevier B.V. All rights reserved.

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an Aero S Feeder ((Mastersizer 3000, Malvern Instruments, Westborough, MA). Approximately 0.5 g of sample was taken for each analysis. All the measurements were performed in triplicate.

entrapped air during the compression process to avoid tablets defects. A multi-step tablet compression process is composed of consolidation, compaction, and ejection. Thus, the integrity of the final compact depends on the initial particle rearrangement, particle deformation for the bond formation during the compression, and survival of bonding after the release of the compression pressure. Hence, material deformation under applied compression is another critical component responsible for possible tablet defects (Dwivedi et al., 1992). A capping problem is generally solved using various random approaches with regard to process and formulation perspectives. These approaches include decreasing compression pressure, increasing dwell time, changing the shape of the punch head geometry, and decreasing the punch penetration (Shah, 2019; Dugar, 2019; Çelik, 2016). Other remedies to reduce the capping behavior consist of decreasing the percent fines in the powder blend and using high fractions of plastically deforming excipients (Dudhat et al., 2017; Thoorens, 2014). However, these trial and error approaches cannot guarantee a successful troublefree and smooth tablet manufacturing operation. Therefore, it is necessary to establish qualitative and quantitative relationships of powder blend and deformation properties with a capping tendency of the respective formulation. This comprehensive approach can certainly help to decode the relationships of these material properties with capping behavior. The objective of this work was to identify and quantify the critical powder rheological and deformation properties responsible for tablet capping of model active pharmaceutical ingredients (APIs) such as acetaminophen (APAP) and ibuprofen using multivariate methods. The powder rheological properties studied included air pressure drop, cohesion, and permeability. The analyzed powder deformation properties were tablet porosity, Brinell hardness, maximum internal air pressure, and tensile strength. The capping score was calculated using the tensile strength and internal air pressure in the tablet. The generated data was modeled using multivariate methods, that included principal component analysis (PCA) and principal component regression (PCR). Finally, the predictive performance of developed PCR calibration models was tested using an independent validation data set containing 40% w/w APAP and IBU formulations.

3.2.2. Powder rheology Prepared powder blends were characterized by using a FT4 Powder Rheometer (Freeman Technology, Worcestershire, UK). Powder cohesiveness and permeability of the entrapped air were measured due to their likely impact on the tablet mechanical behavior and capping potential. 3.2.2.1. Permeability and pressure drop. Permeability is the ability to transmit entrapped air through the powder bed. This measurement was performed by filling the powder blend in a 25 mm × 10 mL split vessel assembly followed by conditioning cycle with the blade of 23.5 mm diameter. The excess powder was scraped out from the assembly. The normal stress of 1, 5, 10, 15, and 20 KPa was applied by a vented piston. A constant air velocity (2 mm/s) was simultaneously supplied to the powder bed by the aeration-controlled unit. The resistance of the powder bed to relieve the air upon the application of normal stress was calculated using Darcy’s law (Eq. (1)) (Durazo-Cardenas et al., 2014). The air flow rate (2.00 cm/s), air viscosity (1.81× 10−5 Pa S), and powder bed length (25.00 mm) were kept constant for all measurements. The relative pressure difference between the top and bottom layer of the powder bed was measured as the pressure drop (PD).

K=

qμL ΔP

(1)

where K is the permeability (cm2), q is the air flow rate (cm/s), µ is the air viscosity (pa s), L is the length of powder bed (cm), and ΔP is the PD across the powder bed (mbar). 3.2.2.2. Powder blend cohesion. A powder blend placed in a 50 mm × 85 mL split vessel was preconditioned prior to each run. This was necessary to ensure a homogenous packing of the powder bed. A powder blend was preconditioned with a sequence of a pre-shearing process. Initially, the powder was over-consolidated at a normal stress of 5 kPa, 10 kPa, 15 kPa, and 20 kPa. This over-consolidated powder was sheared with a corresponding shear stress of 5 kPa, 10 kPa, 15 kPa, and 20 kPa. The upper layer of consolidated powder slipped against the lower layer when the shear force was increased to the yield point. A total of 4 Mohr’s circles were generated from the shear versus normal stress data, and respective critical shear stresses (Ƭfs ) were computed. Critical shear stress is the maximum shear stress handled by powder without failure under the applied normal stress (σ ). These critical shear stresses were used to construct a Coulomb failure criterion. Four Mohr’s circles were constructed to check the linearity of the Coulomb failure criterion line. Finally, the powder cohesion (C) was calculated from the Y-intercept using Eq. (1) (Aulton and Taylor, 2017; Berry et al., 2015).

2. Materials Acetaminophen (Lot no. 1605250016) was purchased from Letco Medical LLC (Decatur, AL). Ibuprofen (Lot no. 16K16-U432-034139) was purchased from Fagron Inc. (St Paul, MN). EMCOCEL® 50M [microcrystalline cellulose (MCC)] was purchased from (JRS Pharma LP, Patterson, NY) and magnesium stearate was purchased from SigmaAldrich (St. Louis, MO). All the samples were used as obtained. 3. Methods 3.1. Blend preparation Drug-excipient blends of APAP and IBU were prepared by mixing with EMCOCEL® 50M. APAP and EMCOCEL® 50M were blended in the fractions of 10.0% w/w to 70.0% w/w. IBU and EMCOCEL® 50M were blended in the fractions of 10.0% w/w to 80.0% w/w. Materials were blended using a V – blender (Globe Pharma Inc., New Brunswick, NJ) at 20.0 rpm for 8 min. The resulting blends were lubricated with 1.0% w/ w magnesium stearate. This mixture was blended for an additional 2 min. More than 50% of the tablets were capped when APAP and IBU fractions were above 70% w/w and 80.0% w/w, respectively.

Ƭfs = C + σ tanθ

(2)

where C is the cohesion and θ is the friction angle. Shear strength is composed of cohesion and frictional angle. Higher values of C and θ indicate high cohesion, high friction angle, and high shear strength. A noncohesive material is characterized when C = 0. Powders with a high shear strength are difficult to flow.

3.2. Power micrometrics

3.2.2.3. Particle density. Particle density was measured with a helium displacement pycnometer (Ultrapyc1200e, Quantacrome Instruments, Boynton Beach, FL). Ten repetitive purge cycles for each sample were performed before recording the particle density. Particle densities were measured as the average of three.

3.2.1. Particle size analysis Particle size distributions of APAP, IBU, and EMCOCEL® 50M were measured using a laser diffraction particle size analyzer coupled with 2

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pressure in the tablet was calculated using Equation 7 (Zavaliangos, 2017).

3.3. Tablet preparation Tablets of 300 mg were compressed on 8-station Piccola press (Riva Europe Ltd, Aldershot, Hampshire, UK.) using 10 mm flat faced punches at 40 rpm. Fifteen formulations of APAP and IBU were compressed at 100 MPa, 200 MPa, and 300 MPa.

P = P0

3.8. Capping score

Initially, tablet dimensions for the tablet density (Eq. (3)) determinations were measured with a vernier caliper (Sigma-Aldrich, St. Louis, MO). Tablet porosity was measured using Eq. (4) (Aulton and Taylor, 2017).

Tablet mass (g ) Tablet volume (cm3)

The capping score of APAP and IBU tablets was calculated using Eq. (8) (Zavaliangos, 2017). This is a unitless number. Tablets having a capping score between 0.1 and 0.6 were found to have low or no capping tendency. A capping score above 0.6 led to tablet capping.

(3)

Tablet density (g / cm3) Tablet porosity = 1 − Particle density (g / cm3)

(7)

where Po is the initial air pressure (atmospheric pressure, Patm: 0.10135 MPa), D0 is the initial relative density of the powder blend (g/ mm3), and D is the final relative density of the compact (g/mm3).

3.4. Tablet porosity

Tablet density =

1 − D0 D 1 − D DD0

Capping score = (4)

Pmax TS

(8)

where Pmax is the maximum air pressure in the tablet (MPa) and TS is the tablet tensile strength (MPa).

3.5. Brinell hardness 3.9. Statistical analysis Hardness is defined as the resistance of a compact to a local permanent deformation upon the application of external pressure (Çelik, 2016). It was measured using a spherical indentation probe (3.18 mm in diameter) attached to a texture analyzer (TA-XT2i, Texture Technologies Corp, Scarsdale, NY). The tablet was placed horizontally on the flat surface. A force of 40 N at a speed of 0.01 mm/s was applied with the indentation probe normal to the tablet plane. An applied force was set at 40 N to maintain tablet integrity containing a higher percentage of APAP and IBU. Indentation dimensions were measured using a calibrated digital microscope (~X230 magnification, Dino-Lite TM Pro AM413MT; AnMo Electronics Corporation, New Taipei, Taiwan). The circumference of the indent was fitted by the three-point method (Chang and Sun, 2017). The indentation area was calculated with Dino Capture TM software (v2.0 An MO Electronics Corporation, Hsinchu300, Taiwan). BH was calculated using Eq. (5).

BH =

F A

The data were analysed qualitatively and quantitatively with a principal component analysis (PCA) and a principal component regression (PCR) models, respectively, using Unscrambler® v10 software (CAMO Software AS, Trondheim, Norway). Individual values were used in the PCA and PCR modeling to induce variability in the data. All the data set was used for a qualitative PCA, which decodes hidden data patterns such as sample grouping, similarities, and differences (Haware, 2014). A quantitative PCR was performed by separating data set into a calibration set and a validation set. PCR was used to quantify the impact of the main effects of various design variables, such as material type, compression pressure, pressure drop across the powder, powder cohesiveness, powder permeability, tablet porosity, tablet hardness, and tablet air pressure. The Y-variable was the capping score. The experimental data set consisting of 40.00% w/w of APAP and IBU was assigned as a “validation set”. The predictive modeling performance of the PCR model was tested with an independent validation data set. All other remaining experimental data was assigned as a “calibration set”. The design and response variables were weighted and scaled by dividing with their standard deviation before each PCA and PCR modeling. The material types (EMCOCEL® 50M, APAP, and IBU) were coded as category variables and coded as “0” and “1” during PCR analysis. This was done to separate the impact of the materials on the capping score. The uncertainty of the PCR coefficient was estimated with the full cross-validation and Jack-Knifing method (Martens and Martens, 2000). Additionally, the statistically significant differences of computed capping score were quantified using a two-way analysis of variance. Capping scores having a p-value of less than 0.05 were termed as statistically different from each other.

(5) 2

where BH is the Brinell hardness (N/mm ), F is the force (N), and A is the measured tablet area (mm2). 3.6. Tablet tensile strength A diametrical crushing force required to break a tablet was measured with a TA-54 texture analyzer probe (TA-XT2i, Texture Technologies Corp, Scarsdale, NY). The tablet was placed diametrically on the flat surface. Pre-test speed of the probe was set to 0.5 mm/s. The test speed was set to 1.0 mm/s for all the tests. The tablet dimensions were measured with a vernier caliper (Sigma-Aldrich, St. Louis, MO). Test conditions were kept constant for all the runs. Tablet tensile strength was calculated with Eq. (6) (Fell and Newton, 1970).

σT =

2F πDH

4. Results and discussion Tablet capping was studied with a poorly compressible model of elastically deforming APIs such as APAP and IBU (Fig. 1). A particle size distribution analysis of these elastic (IBU and APAP) and plastic (EMCOCEL® 50M) materials revealed that these materials could be arranged in descending order according to their particle size distribution (d50) as follows: EMCOCEL® 50M [d50 = 68.20 µm] > IBU [d50 = 59.60 ( ± 2.01) µm] > APAP [d50 = 32.60 ( ± 1.64) µm] APAP and IBU powders were blended with a commonly used plastically deforming excipient, namely EMCOCEL® 50M, to understand the powder blend’s ability to yield the capping behavior. A 100-tablet batch was compressed at each fraction of APIs (10% w/w to 100% w/w).

(6)

where σT is tablet tensile strength (MPa), F is the force required to initiate the fracture (N), D is the diameter of the tablet (mm), and H is the thickness of the tablet (mm). 3.7. Internal air pressure of the tablet The powder relative density and the resulting compressed tablet relative density were measured to calculate the upper bound of entrapped air pressure in the compressed tablet. Air pressure in the powder blend was considered as atmospheric pressure, and the air 3

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Fig. 1. Pictographs of capped and intact tablets. A = EMCOCEL® 50M intact tablets; B = APAP intact tablets; C = APAP capped tablets; D = IBU intact tablets; E = IBU capped tablets.

4.2. Qualitative analysis of powder properties and tablet properties on capping score

However, more than 50% of the tablets were capped at higher fractions of APIs. To maintain the accuracy of the results, higher fractions of API batches were excluded in the study. APAP blends were studied in fractions of 10.0% w/w to 70.0% w/w, and IBU blends were studied in fractions of 10.0% w/w to 80.0% w/w. The APAP tablets started exhibiting capping behavior when the amount of APAP reached above 50% w/w in the formulation, regardless of applied compression pressure. The IBU tablets were not capped when compressed at the 100 MPa. However, tablets containing more than 20% w/w IBU exhibited capping after compressing at 200 MPa and 300 MPa. As expected, tablets containing 100% w/w EMCOCEL® 50M have maintained their integrity at the compression pressures studied.

Initially, the data pattern (Tables 1–3.) was decoded with a qualitative PCA. The samples (plain EMCOCEL® 50M, APAP and IBU blends compressed at 100, 200, and 300 MPa compression pressures), and variables (powder and tablet properties) located on the same side of the principal components (PCs) of scores plot and loadings plot, respectively, were positively correlated, while those located on the opposite side of PCs showed an inverse correlation (Fig. 2A and B). Seven PCs were employed to explain a 100% variation in the data. The first two PCs explained 69% of the variation in the data. The PCA score plot (Fig. 2A) exhibited sample patterns, groupings, similarities, and differences, while the PCA loading plot (Fig. 2B) indicated the factors responsible for the groupings in the PCA score plot. Thus, these two plots needed to be analyzed simultaneously to decode the qualitative relationships hidden in the data. The PCA score plot (Fig. 2A) showed three distinct groups of studied materials (plain EMCOCEL® 50M, APAP, and IBU) along the PC1 axis. Group 1 was composed of plain EMCOCEL® 50M tablets, which formed a distinct grouping in the right lower down corner of the PCA score plot (Fig. 2A). It indicated different powder rheological and tableting behavior than those prepared with APAP and IBU. This group showed a positive correlation with the powder permeability. This can be attributed to the higher number of air-escaping channels in the powder blend. A negative correlation of EMCOCEL® 50M with the cohesion and pressure drop again supports the availability of a higher number of escaping channels. Cohesiveness is the inter-particulate attraction in the powder blend that provides the internal shear strength. Shear strength is defined as the resistance of the particles to move parallel to the cross-sectional area. A lesser shear strength increases the particle parallel movement and thereby increases the number of channels for air to escape. Hence, powders that are less cohesive are characterized by a lower pressure drop and a corresponding high permeability. Group 1 also showed an expected strong correlation with the studied tableting properties, such as porosity, internal air pressure, Brinell hardness, and tensile strength. This can be attributed to the bond favoring predominantly plastically deforming behavior of EMCOCEL® 50M (David and Augsburger, 1977). The placement of tablet internal air pressure, Brinell hardness, and tensile strength in the lower right corner of the PCA loading plot along the PC1 axis indicated a strong correlation between these parameters. A stronger compact characterized by high tensile strength and Brinell hardness appears to have high internal air pressure. Such high air internal air pressure inside the stronger compacts might not lead to a crack propagation due to high bonding strength (Zavaliangos, 2017). However, internal tablet air pressure must be rationalized with the tensile strength to check whether this air pressure can cause a crack in the compact to lead to capping behavior. A positive correlation with the tablet properties of Brinell hardness, tensile strength, and IAP, as well as with the powder property

4.1. Estimation of capping score Conventional capping score is calculated as a ratio of the number of tablets that are capped during the compression and the breaking force test process to the total number of tablets compressed (Shah, 2019). But this method depends on the operator’s skill and does include material behavior responsible for the capping. It is well discussed in the literature that capping behavior is known to be a function of air entrapment and tablet mechanical behavior. A tablet mechanical behavior was estimated by tensile strength (resistance of a tablet to initiate the fracture) using Eq. (6). While a reduction in the tablet tensile strength was attributed to capping behavior, there was no universal tensile strength value below which capping behavior was evident. This was also observed with the two model materials that yielded capping behavior at different tensile strength values. This phenomenon suggested the possible interference of tablet internal air pressure to the integrity of the tablet. An upper bound limit of the tablet internal air pressure was calculated using Eq. (7). Then again, the question that arises is, how much air pressure can cause a crack in the tablet? For example, at 100 MPa compression pressure, a plain EMCOCEL® 50M tablet showed 6.36 MPa of tensile strength and 2.14 MPa of internal air pressure, which is 20 times the atmospheric pressure. At 200 MPa compression pressure, a plain EMCOCEL® 50M tablet showed 8.77 MPa of tensile strength and 3.12 MPa of air pressure, which is 30 times the atmospheric pressure. However, the above mentioned two tablets did not show capping behavior, indicating that higher pressure does not lead to capping behavior. To clarify, the authors looked for the level of internal air pressure that can cause cracking and it was decided that a reasonable approach must be made to compare the entrapped air pressure with the tolerable limits of the tablet tensile strength. To provide a solution, the ratio of maximum tablet internal air pressure to the tablet tensile strength was calculated to compute the capping score (Eq. (8)). A qualitative and quantitative relationship of the powder rheological properties (permeability, pressure drop, and cohesion), and tablet properties (porosity, Brinell hardness, internal air pressure, and tensile strength) [Tables 1–3.] with a computed capping score were evaluated using PCA and PCR multivariate methods, respectively. 4

International Journal of Pharmaceutics 569 (2019) 118548

6.36 (0.25) 8.77 (0.12) 7.90 (0.22)

0.34 (0.01) 0.36 (0.02) 0.39 (0.01)

of permeability, suggested that EMCOCEL® 50M tablets are much stronger and less prone to capping behavior. Group 2 was composed of tablets formulated with a 10% w/w APAP, 20% w/w APAP, 10% w/w IBU, 20% w/w IBU, 30% w/w IBU, and 40% w/w IBU at all studied compression pressures. It also consisted tablets of 50% w/w, and 60% w/w IBU compressed at 100 MPa. This group spanned the right side across the PC1 (Fig. 2A). Group 2 exhibited a similar positive correlation to powder permeability and other tableting properties such as porosity, internal air pressure, Brinell hardness, and tensile strength. A negative correlation was observed with API amount, powder pressure drop, powder cohesion, compression pressure, and capping score. It is important to note that similar powder properties and tablet properties were observed for Group 1 and Group 2. This may be because of the higher amount of EMCOCEL® 50M fraction in these formulations. However, Group 1 and Group 2 were on the same side, and they exhibited a similar relationship with the powder and tablet properties; they were distinctly separated from each other. This can be observed with the different PC1 scores. Group 1 was located between the PC1 score from 5 to 6, whereas Group 2 was located between the PC1 score from 1 to 2.5. This indicates the powder and tablet properties responsible for the similar location of the Group 1 and Group 2 are much stronger in Group 1 with a higher PC1 score, whereas these properties were minimized in Group 2 with a lower PC1 score. Formulations in Group 2 were observed to be weaker than Group 1. This can be ascribed to the replacement of the bond-favoring plastic EMCOCEL® 50M with the smaller amount of elastic APAP and IBU in Group 2 (Nokhodchi, 1995; Garekani, 2001). Regardless of a similar effect of powder permeability, Brinell hardness, tensile strength, and IAP based on the grouping along the PC1 axis, within Group 2 these two model materials (APAP and IBU) were clearly separated along the PC2 axis. The IBU formulations in Group 2 were strongly correlated with the powder permeability (located on the upper side of the PC 2 axis), whereas the APAP formulations were strongly correlated with the tablet properties, such as Brinell hardness and tensile strength, and IAP (located on the lower side of the PC 2 axis). This suggested that these twomodel materials exhibit different powder and tablet properties. For this reason, two independent quantitative relationships were developed for APAP and IBU in the following sections. A Group 3 was composed of tablet formulations containing 30 to 70% w/w APAP, 70% w/w IBU, and 80% w/w IBU at all studied compression pressures. This group also included 50% w/w and 60% w/ w IBU compressed at 200 and 300 MPa (Fig. 2A). These formulations showed a positive correlation with compression pressure, API amount, pressure drop, and capping score along PC1 and indicated a higher capping tendency than the formulations falling in the first and second group. This can be attributed to replacing EMCOCEL® 50M with higher amounts of poorly compressible APIs (Nokhodchi, 1995; Garekani, 2001). It is also important to note a distinct placing of APAP, IBU, and EMCOCEL® 50M in the PCA loading plots. This confirms their anticipated different capping tendencies. APAP exhibited a higher capping tendency than IBU and EMCOCEL® 50M. APAP also showed a strong positive correlation with powder cohesion and air pressure drop in the lower left side corner of the PCA loadings plot. Thus, a high air entrapment and powder cohesiveness might be the predominant factors for the capping tendency of APAP (Dudhat et al., 2017). Furthermore, a positive correlation of APAP with a compression pressure and capping tendency suggests its high capping tendency with an increased compression pressure. On the other hand, a negative correlation of most of the tableting properties (the tablet internal air pressure, Brinell hardness, and tensile strength) of IBU along PC1 to capping score may imply that IBU capping behavior is primarily dominated more by its tableting properties than its powder behavior (Nokhodchi, 1995). This is also confirmed with a positive correlation of IBU with a powder permeability along the PC1 axis. A positive correlation of IBU with powder permeability indicates that IBU powder is less cohesive than APAP. A negative correlation of IBU with a compression pressure and capping

Note: The results are given as a mean of three experiments for each formulation, and the standard deviation is mentioned in the parentheses.

2.14 (0.02) 3.12 (0.05) 3.10 (0.06) 56.12 (1.16) 66.74 (1.21) 58.23 (0.35) 0.22 (0.04) 0.15 (0.06) 0.16 (0.02) 185.35 (3.16) 185.35 (3.16) 185.35 (3.16) Plain EMCOCEL® 50M Plain EMCOCEL® 50M Plain EMCOCEL® 50M

100 200 300

0.95 (0.02) 0.95 (0.02) 0.95 (0.02) 0 0 0 EMCOCEL® 50M EMCOCEL® 50M EMCOCEL® 50M

1.98 (0.06) 1.98 (0.06) 1.98 (0.06)

Capping Score# Tensile Strength (MPa) Air Pressure (MPa) Brinell Hardness (MPa) H E C

D B A

F

G

Tablet Properties Powder Properties Experimental Design

Table 1 All the experimental results from the powder rheological and tablet mechanical behavior of EMCOCEL® 50 M blends [A = Material type, B = API fraction (% w/w), C = Formulation, D = Compression pressure (MPa), E = Pressure drop across the powder bed (mbar), F = Powder cohesion (kPas), G = Powder permeability (cm2), H = Porosity, # = Statistically significant with a p value less than 0.05].

P. Basim, et al.

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Table 2 All the experimental results from the powder rheological and tablet mechanical behavior of APAP blends [A = Material type, B = API fraction (% w/w), C = Formulation, D = Compression pressure (MPa), E = Pressure drop across the powder bed (mbar), F = Powder cohesion (kPas), G = Powder permeability (cm2), H = Porosity, # = Statistically significant with a p value less than 0.05]. Experimental Design A

B

C

APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP

10 10 10 20 20 20 30 30 30 40 40 40 50 50 50 60 60 60 70 70 70

10% 10% 10% 20% 20% 20% 30% 30% 30% 40% 40% 40% 50% 50% 50% 60% 60% 60% 70% 70% 70%

Powder Properties

APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP APAP

D

E

100 200 300 100 200 300 100 200 300 100 200 300 100 200 300 100 200 300 100 200 300

0.76 0.76 0.76 0.89 0.89 0.89 1.18 1.18 1.18 1.34 1.34 1.34 1.62 1.62 1.62 1.89 1.89 1.89 2.20 2.20 2.20

Tablet Properties

F (0.06) (0.06) (0.06) (0.05) (0.05) (0.05) (0.08) (0.08) (0.08) (0.11) (0.11) (0.11) (0.15) (0.15) (0.15) (0.09) (0.09) (0.09) (0.19) (0.19) (0.19)

1.49 1.49 1.49 1.91 1.91 1.91 2.31 2.31 2.31 3.25 3.25 3.25 2.85 2.85 2.85 2.34 2.34 2.34 3.28 3.28 3.28

(0.02) (0.02) (0.02) (0.05) (0.05) (0.05) (0.11) (0.11) (0.11) (0.12) (0.12) (0.12) (0.16) (0.16) (0.16) (0.22) (0.22) (0.22) (0.21) (0.21) (0.21)

G

H

156.63 (6.27) 156.63 (6.27) 156.63 (6.27) 126.31 (5.94) 126.31 (5.94) 126.31 (5.94) 94.21 (4.62) 94.21 (4.62) 94.21 (4.62) 79.75 (6.12) 79.75 (6.12) 79.75 (6.12) 62.23 (3.65) 62.23 (3.65) 62.23 (3.65) 51.86 (4.15) 51.86 (4.15) 51.86 (4.15) 43.68 (5.47) 43.68 (5.47) 43.68 (5.47)

0.15 0.11 0.12 0.17 0.11 0.12 0.16 0.12 0.13 0.17 0.12 0.13 0.17 0.12 0.14 0.17 0.13 0.14 0.18 0.14 0.15

(0.01) (0.03) (0.03) (0.02) (0.04) (0.04) (0.04) (0.01) (0.03) (0.02) (0.01) (0.02) (0.05) (0.02) (0.01) (0.03) (0.01) (0.02) (0.02) (0.01) (0.01)

Brinell Hardness (MPa)

Air Pressure (MPa)

Tensile Strength (MPa)

Capping Score#

55.37 (1.27) 61.87 (2.12) 58.04 (0.02) 55.06 (1.34) 59.03 (1.92) 52.69 (0.06) 52.66 (2.11) 56.69 (2.14) 43.6 (0.25) 48.34 (1.34) 54.20 (0.65) 42.63 (0.45) 45.43 (0.82) 49.08 (1.56) 41.58 (0.85) 43.09 (0.96) 43.43 (0.88) 39.67 (0.92) 41.04 (1.85) 42.10 (1.65) 36.18 (1.25)

1.97 2.21 1.85 1.51 1.92 1.98 1.49 1.58 1.68 1.34 1.79 1.78 1.30 1.54 1.53 1.23 1.33 1.39 1.27 1.25 1.41

4.26 (0.08) 6.22 (0.19) 5.72 (0.02) 3.29 (1.02) 4.78 (0.25) 3.08 (0.21 2.64 (0.11) 3.39 (0.21) 2.76 (0.14) 2.29 (0.15) 3.59 (0.18) 2.84 (0.16) 1.74 (0.18) 2.4 (0.16) 2.28 (0.02) 1.07 (0.16) 1.64 (0.15) 1.67 (0.13) 0.91 (0.28) 1.13 (0.31) 1.06 (0.21)

0.46 0.36 0.32 0.46 0.40 0.64 0.57 0.47 0.61 0.59 0.50 0.63 0.75 0.64 0.68 1.15 0.81 0.83 1.40 1.11 1.32

(0.01) (0.03) (0.02) (0.02) (0.01) (0.02) (0.02) (0.05) (0.04) (0.04) (0.03) (0.01) (0.01) (0.02) (0.02) (0.05) (0.02) (0.01) (0.01) (0.02) (0.03)

(0.01) (0.02) (0.02) (0.02) (0.01) (0.04) (0.01) (0.04) (0.02) (0.02) (0.01) (0.01) (0.03) (0.02) (0.02) (0.02) (0.03) (0.05) (0.05) (0.03) (0.04)

Note: Results are given as a mean of three experiments for each formulation, and the standard deviation is mentioned in the parentheses.

4.3. Quantitative analysis of powder properties and tablet properties on capping score

score along the PC1 axis also suggests that IBU tablet capping could be aggravated with an application of higher compression pressure. All these qualitative correlations were further quantified using a PCR analysis to distinguish which of these properties significantly affect the capping behavior.

Qualitative relationships identified with PCA analysis were quantified with PCR (Fig. 3A and B). Quantitative influences of the main effects of the API amount and type, powder rheological properties (permeability, pressure drop, and cohesion) and tableting properties (porosity, Brinell hardness, and tensile strength) on the capping score of

Table 3 All the experimental results from the powder rheological and tablet mechanical behavior of IBU blends [A = Material type, B = API fraction (% w/w), C = Formulation, D = Compression pressure (MPa), E = Pressure drop across the powder bed (mbar), F = Powder cohesion (kPas), G = Powder permeability (cm2), H = Porosity, # = Statistically significant with a p value less than 0.05]. Experimental Design A

B

C

IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU

10 10 10 20 20 20 30 30 30 40 40 40 50 50 50 60 60 60 70 70 70 80 80 80

10% 10% 10% 20% 20% 20% 30% 30% 30% 40% 40% 40% 50% 50% 50% 60% 60% 60% 70% 70% 70% 80% 80% 80%

IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU IBU

Powder Properties D

E

100 200 300 100 200 300 100 200 300 100 200 300 100 200 300 100 200 300 100 200 300 100 200 300

0.79 0.79 0.79 0.82 0.82 0.82 0.84 0.84 0.84 0.90 0.90 0.90 0.90 0.90 0.90 0.92 0.92 0.92 0.93 0.93 0.93 0.96 0.96 0.96

Tablet Properties

F (0.04) (0.04) (0.04) (0.08) (0.08) (0.08) (0.07) (0.07) (0.07) (0.12) (0.12) (0.12) (0.15) (0.15) (0.15) (0.16) (0.16) (0.16) (0.12) (0.12) (0.12) (0.16) (0.16) (0.16)

0.96 0.96 0.96 1.00 1.00 1.00 1.03 1.03 1.03 1.16 1.16 1.16 1.36 1.36 1.36 1.36 1.36 1.36 1.44 1.44 1.44 1.52 1.52 1.52

G (0.04) (0.04) (0.04) (0.12) (0.12) (0.12) (0.07) (0.07) (0.07) (0.11) (0.11) (0.11) (0.08) (0.08) (0.08) (0.04) (0.04) (0.04) (0.07) (0.07) (0.07) (0.06) (0.06) (0.06)

154.04 154.04 154.04 156.73 156.73 156.73 145.38 145.38 145.38 153.47 153.47 153.47 135.29 135.29 135.29 128.33 128.33 128.33 129.92 129.92 129.92 132.34 132.34 132.34

(2.26) (2.26) (2.26) (3.11) (3.11) (3.11) (2.26) (2.26) (2.26) (2.21) (2.21) (2.21) (3.34) (3.34) (3.34) (1.26) (1.26) (1.26) (1.65) (1.65) (1.65) (2.26) (2.26) (2.26)

H

Brinell Hardness (MPa)

Air Pressure (MPa)

Tensile Strength (MPa)

Capping Score#

0.17 (0.01) 0.14 (0.02) 0.16 (0.01) 0.16 (0.01) 0.14 (0.01) 0.15 (0.01) 0.17 (0.02) O.17 (0.01) 0.16 (0.02) 0.17 (0.01) 0.18 (0.02) 0.19 (0. 01) 0.17 (0.02) 0.18 (0.01) 0.18 (0.01) 018 (0.01) 0.18 (0.01) 0.19 (0.02) 0.19 (0.01) 0.19 (0.01) 0.20 (0.01) 019 (0.02) 0.20 (0.01) 0.23 (0.01)

45.52 41.28 34.23 42.53 40.39 31.17 42.28 36.80 25.78 42.53 36.80 24.74 40.39 35.62 23.63 35.62 34.37 22.87 34.37 34.32 22.54 34.32 30.52 19.13

1.69 1.77 1.81 1.43 1.62 1.61 1.39 1.49 1.59 1.37 1.45 1.44 1.16 1.27 1.27 1.08 1.18 1.24 1.04 1.03 1.17 0.92 0.90 1.09

2.93 2.55 2.17 2.61 2.34 1.93 2.39 2.22 1.84 2.38 2.31 1.62 2.14 2.10 1.53 1.97 1.84 1.49 1.78 1.58 1.29 1.55 1.35 1.01

0.58 0.69 0.84 0.55 0.69 0.83 0.58 0.67 0.86 0.58 0.63 0.89 0.54 0.60 0.83 0.55 0.64 0.83 0.59 0.65 0.91 0.59 0.67 1.07

(1.55) (0.98) (0.89) (1.25) (1.26) (0.81) (0.63) (1.66) (0.58) (1.21) (1.29) (0.35) (0.62) (0.98) (0.56) (0.64) (0.67) (0.89) (0.82) (1.25) (1.22) (0.32) (0.28) (1.85)

(0.02) (0.03) (0.04) (0.04) (0.01) (0.02) (0.02) (0.01) (0.03) (0.01) (0.02) (0.01) (0.02) (0.01) (0.02) (0.02) (0.04) (0.02) (0.01) (0.02) (0.04) (0.01) (0.02) (0.03)

(0.12) (0.12) (0.24) (0.23) (0.25) (0.31) (0.28) (0.17) (0.19) (0.26) (0.36) (0.18 (0.47) (0.51) (0.05) (0.25) (0.62) (0.61) (0.25) (0.12) (0.22) (0.14) (0.02) (0.24)

Note: Results are given as a mean of three experiments for each formulation, and the standard deviation is mentioned in the parentheses. 6

(0.01) (0.02) (0.04) (0.02) (0.03) (0.04) (0.01) (0.02) (0.02) (0.03) (0.01) (0.04) (0.02) (0.02) (0.02) (0.01) (0.02) (0.04) (0.05) (0.04) (0.04) (0.04) (0.03) (0.04)

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Fig. 2. The principal component analysis (A) Score plot; and (B) Loadings plot of powder and tableting properties of EMCOCEL® 50M, APAP, and IBU formulations. The first two principal components represent 69% of the variance in the data. A total of seven principal components explained the 100% variance in the data — [IAPInternal air pressure of tablet (MPa)].

Fig. 3. The principal regression analysis plot of (A) APAP; and (B) IBU indicating weighted regression coefficients of main effects of all X–variables (material type, API amount, compression pressure, pressure drop across the powder, powder cohesion powder permeability, internal air pressure of the tablet (IAP), tablet, tablet porosity, tablet Brinell hardness, tablet tensile strength) on the Y-variable (tablet capping score). The model statistical significance (α = 0.05) was determined by full cross-validation and Jack-Knifing (Murdande et al., 2015). The regression coefficient with error bars that does not pass through the origin are statistically significant.

4.3.1. Quantification of capping score in the APAP formulations The PCR model of APAP (Fig. 3A) was optimized with seven PCs that explained the 98% and 74% variance in the X- and Y-data, respectively. The first two PCs explained 77% and 62% variance in the Xand Y-data, respectively. The root means square error (RMSE) at the calibration stage and the prediction stage was 0.16 and 0.18, respectively. The model coefficient of determination (R2) at the calibration stage was 0.74, and at the prediction stage was 0.71. The regression equation of developed PCR model of capping score of APAP is given in Eq. (9).

APAP and IBU were studied. As highlighted earlier, the two model materials (APAP and IBU) clearly separated within Group 2 and Group 3 along the PC 2 axis. This indicated that APAP and IBU exhibited different behaviors. As a result, two separate optimized PCR models were developed with the common excipient EMCOCEL® 50M. The authors were aware that PCR is also used to quantify interactions and square effects (Talekar et al., 2019). However, interactions and square terms were not used as the primary purpose of this modeling. A statistically significant impact of the X-variables on the Y-variable was identified with 95% confidence interval bars. Statistically insignificant variables were characterized with a 95% confidence interval bars crossing the zero line. The sign and magnitude of the coefficient bar indicated the impact of significant variables on the Y-variable. The statistical significance of the model was determined at p < 0.05 (Gupte, 2017). Positive regression coefficients indicate a positive effect on the capping score and vice versa.

APAP capping score ® = 0.5346 + 0.0910 (EMCOCEL50M) − 0.0910(APAP ) + 0.0028

(API amount ) + 0.1732(PD) + 0.0672(Cohesion) − 0.0011 (Permeability ) − −0.0134(TS )

(9)

where PD is pressure drop (mbar), IAP is the internal air pressure 7

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Fig. 4. Comparisons of the capping score of the APAP and IBU at a compression pressure of (A). 100 MPa; (B) 200 MPa; (C) 300 MPa. The capping scores of APAP and IBU exhibited a reverse trend at critical fractions, which varied with the applied compression pressure. (n = 3).

the capping score. Highly permeable powders exhibit a higher number of air escaping channels to relieve the high amount of air, resulting in stronger tablets (Zavaliangos, 2017). Furthermore, an inverse relationship between cohesion and permeability suggests that highly cohesive powder blends with a smaller number of air escaping channels exhibit less permeability and entrap more air. The main effect of tensile strength showed a negative impact on the capping score. This means that stronger tablets have a tendency for less capping and could maintain their integrity during the entire tableting operations. It is also important to note that tensile strength is the result of powder rheological and tablet mechanical behavior (Dudhat et al., 2017). Except for tablet tensile strength, none of the tablet properties like porosity, tablet internal air pressure, compression pressure, and Brinell hardness showed any statistically significant effect on the capping score. This could indicate that the capping tendency of APAP is predominantly due to its powder air entrapment behavior.

(MPa), BH is the Brinell hardness (MPa), and TS is tensile strength (MPa). EMCOCEL® 50M and APAP (Fig. 3A) in the tablet formulation exhibited a respective positive and negative impact on the capping score. It is expected that a predominant plastically deforming EMCOCEL® 50M as a binder could lead to form stronger tablets, which could maintain their integrity during handling. Thus, a high amount of EMCOCEL® 50M is expected to form a tablet with a low capping score. However, this opposite effects of EMCOCEL® 50M and APAP on the capping score can be explained with Fig. 4. As seen in Fig. 4, the impact of APAP amount in the APAP-EMCOCEL® 50M blend followed an exponential relationship after a crossover point. A crossover point is the inflection point from which the high capping behavior of formulation is observed. This crossover point was observed at 40, 50, 60 %w/w APAP at 100, 200, 300 MPa compression pressure, respectively. Below this crossover point, the amount of EMCOCEL® 50M in the formulation is more than APAP, which is mainly responsible for the displayed capping score. These data points are more than those after crossover points in the developed models. Therefore, this model might be exhibiting respective negative and positive impacts of EMCOCEL® 50M and APAP on the capping score. The API amount showed a positive impact on the capping score and can be attributed to an increased amount of poorly compressible APAP in the formulation and a decreased amount of highly compressible EMCOCEL® 50M. This dominance of the APAP amount on capping score was also confirmed in the qualitative PCA where the APAP, the amount of API and the capping scores positively correlated, while lower fractions of APAP (up to 20% w/w) in the formulations are inversely correlated to the capping scores along the PC1. This may be because of capping behavior exhibited only at higher fractions of APAP (above 50% w/w APAP) or after the crossover point. The powder rheological properties, such as pressure drop and powder cohesion, displayed a significantly positive impact, while powder permeability showed a significantly negative impact on the APAP capping score. Pressure drop is the pressure gradient developed across the powder bed and shows the inability of the powder blend to relieve the entrapped air (Dudhat et al., 2017). A high-pressure drop indicates a high amount of air in the powder blend. This entrapped air in the powder blend can cause particle separation, which can lead to insufficient interparticulate bonding and resulting in a poor tablet (Zavaliangos, 2017). Another powder rheological property the authors studied was powder cohesion, which is the attraction of energy among the particles (Dudhat et al., 2017). High cohesive energy leads to strong bonding among the particles, which does not allow the parallel movement of the particles to the cross-sectional area. This reduces the availability of air escaping channels in the powder bed. As a consequence, a high cohesion could lead to high air entrapment, and subsequently, high capping behavior. The main effect of air permeability in the powder blend showed a negative impact on

4.3.2. Quantification of capping score in the IBU formulations The PCR model of IBU (Fig. 3B) was optimized with seven PCs, which explained 98% and 86% variance in the X- and Y-data, respectively. The first two PCs explained 82% and 53% variance in the X and Y-data matrix. The root means square error (RMSE) at the calibration stage and the prediction stage was 0.06 and 0.07, respectively. The model coefficient of determination (R2) was observed to be 0.87 at the calibration stage, and 0.85 at the prediction stage. The regression equation of the developed PCR model of the IBU capping score is given in Eq. (10).

IBU capping score ® = 0.9376 − 0.0510(EMCOCEL50M) + 0.0510(IBU ) + 0.0010

(CP ) − 0.0006(Permeability ) − 0.8512(Porosity ) − 0.0045 (BH ) − 0.0093(TS )

(10)

where CP is compression pressure (MPa), BH is the Brinell hardness (MPa), and TS is the tensile strength (MPa). The PCR model of IBU exhibited a negative impact of EMCOCEL® 50M on the capping score. This can be attributed to the predominantly plastic behavior of EMCOCEL® 50M (Thoorens, 2014). It is also important to note that unlike APAP, the IBU capping score is linear as a function of the EMCOCEL® 50M amount in the blend (Fig. 4). The IBU amount showed a positive impact on the capping score. It is known that an increased amount of a predominantly elastic IBU in the formulation blend leads to poor tabletability (Nokhodchi, 1995), and therefore, such tablets exhibit a high capping tendency. The compression pressure showed a significantly positive impact on the capping score, which indicates the applied compression pressure-dependent deformation sensitivity of IBU. Materials used exhibited a high deformation tendency at high compression pressures due to a higher amount of 8

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Fig. 5. The correlation between the measured and predicted capping score of (A) APAP tablet; (B) IBU tablet compressed at a compression pressure of 100 MPa, 200 MPa, and 300 MPa. The capping score was predicted using an optimized principal component regression model.

of APAP may be required to shield EMCOCEL® 50M at high compression pressures.

compression energy on the material. It is well documented that a material with a high deformation in the compression phase is followed by a high elastic recovery in the decompression phase (e.g., starch, MCC). (Jain, 2018) Thus, both predominantly elastic IBU and plastic EMCOCEL® 50M could show a higher deformation in the compression phase, which could be accompanied by a higher elastic recovery in the decompression phase. This could lead to the formation of weaker tablets with a high capping potential. Other material deformation dependent parameters such as tablet porosity, Brinell hardness, and tensile strength exhibited negative impacts on the capping score. It seems that both inter and intraparticulate spaces in the tablet could help to reduce post-compression internal air pressure within the tablet. This could help lower the tablet’s internal air pressure stimulated crack propagation that leads to tablet capping. Brinell hardness and tensile strength showed a negative impact on the capping score. As mentioned previously, hardness is the resistance of the compact to the external pressure for permanent local deformation. High resistance to the external pressure makes the compact less susceptible for the development of cracking (Çelik, 2016; Jain, 1999) that could lead to a lower capping score. Tablet tensile strength is the resistance of the tablet to a diametrical fracture. Thus, stronger tablets are accompanied by a low capping score due to their high structural integrity. It is important to note that powder properties like pressure drop, cohesion, and permeability showed an insignificant correlation to the capping score when IBU blended with EMCOCEL® 50M. This indicated the irrelevant impact of the IBU powder properties on the capping score. This again confirmed that IBU exhibited a deformation-induced capping behavior. As shown in Fig. 4, the overall capping scores of the APAP formulation were lower than the IBU formulations, regardless of the applied compression pressure and the amount of APIs up to a critical fraction of the APAP and IBU. After this critical fraction, APAP showed a higher capping score than IBU. However, this critical fraction changed with the applied compression pressure. The critical fractions for 100 MPa, 200 MPa, and 300 MPa were 40% w/w, 50% w/w, and 60% w/w of the APAP. Formulations containing APAP above these critical fractions exhibited a higher capping score than the IBU. This can be attributed to differences in the particle size of the APAP, IBU, and EMCOCEL® 50M. IBU and EMCOCEL® 50M have relatively smaller differences in their particle size, while the particle size of EMCOCEL® 50M is more than twice as that of APAP. It seems that a smaller-sized APAP could form an even coat around the EMCOCEL® 50M particles with increments in its fractions in the formulations, which could hamper predominant deformation of EMCOCEL® 50M during the compression and lead to the formation of weaker tablets. However, a compression pressure can compensate this shielding effecting of APAP on the EMCOCEL® 50M deformation by providing more energy for the deformation. Therefore, higher fractions

4.4. Evaluation of PCR models predictability Finally, the predictive performance of the developed individual PCR models of APAP and IBU was tested to predict the capping score of tablet formulations containing 40% w/w APAP and IBU. A good correlation between the measured and predicted values of the capping score using optimized PCR models was found (Fig. 5). Fig. 5 shows three groupings of capping scores as a function of the applied compression pressure. As previously described, in the case of both APAP and IBU formulations, a higher compression pressure led to a high capping score. In the case of the APAP formulations (Fig. 5A), the correlation between the measured capping score and the predicted capping score of 40% w/w APAP from the optimized APAP PCR capping score model was 0.85; and the R2 Pearson value was 0.77. On the other hand, the correlation between the measured capping score and the predicted capping score of the 40% w/w IBU formulations from the optimized IBU PCR capping score model (Fig. 5B) was 0.85, and the R2 Pearson value was 0.73. These prediction performances of the optimized models suggest that the evaluated macroscopic powder rheological and tablet mechanical behavior could enable one to quantify a capping tendency of the formulations. 5. Conclusions The present study demonstrated the qualitative and quantitative impact of powder rheological properties (pressure drop in the powder blend, cohesion, and air permeability) and tablet mechanical properties (porosity, internal air pressure of the tablet, Brinell hardness, and tensile strength) on the capping potential of model APIs such as APAP and IBU using multivariate methods. The PCA plots exhibited the capping tendency of APAP and IBU formulations based on the rheological and mechanical properties, respectively. The PCA score plot exhibited three distinct groupings of all the formulations along the PC1, indicating their different capping behaviors. APAP and IBU followed a respective exponential and linear rate pattern concerning their capping score as a function of the applied compression pressure and their respective amounts in the formulations. Therefore, two separate PCR plots were developed to quantify the predominant cause of capping behavior of APAP and IBU. The APAP PCR model showed a statistically significant impact of powder rheological properties, such as powder pressure drop, cohesion, and permeability. It also showed a statistically significant impact on the amount of API. The IBU PCR model exhibited a statistically significant impact of the powder deformation properties, such as tablet porosity, Brinell hardness, and internal air pressure. It 9

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also showed a statistically significant impact of compression pressure and powder permeability. The capping score of both model materials was significantly dependent on the tablet tensile strength. These findings revealed that the capping tendency of APAP was predominantly dependent on its powder properties, while that of IBU was predominantly dependent on its deformation properties. The developed APAP and IBU PCR models predicted the capping score of independent formulation sets containing 40% w/w APAP and IBU based on the applied compression pressure. Thus, the present study established a better understanding of capping behavior with a predictive equation based on powder rheology and deformation, rather than counting the number of tablets capped (conventional capping score) Therefore, the proposed approach can certainly aid in understanding the underlying mechanisms of capping and in developing an effective, optimized strategy to ensure tablet quality.

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Declaration of Competing Interest Author declares that there is no conflicts of interest. Acknowledgement The authors are thankful to Mr. Patrick Campbell for proofreading the manuscript. References Aulton, M.E., Taylor, K.M., 2017. Aulton's pharmaceutics: the design and manufacture of medicines. Elsevier Health Sciences. Berry, R., Bradley, M., McGregor, R., 2015. Brookfield powder flow tester–Results of round robin tests with CRM-116 limestone powder. 3 In: Proceedings of the Institution of Mechanical Engineers, Part E: Journal of Process Mechanical Engineering, pp. 215–230. Çelik, M., 2016. Pharmaceutical powder compaction technology. CRC Press. Chang, S.-Y., Sun, C.C., 2017. Superior plasticity and tabletability of theophylline monohydrate. Mol. Pharm. 14 (6), 2047–2055. David, S.T., Augsburger, L.L., 1977. Plastic flow during compression of directly compressible fillers and its effect on tablet strength. J. Pharm. Sci. 66 (2), 155–159. Dudhat, S.M., Kettler, C.N., Dave, R.H., 2017. To study capping or lamination tendency of tablets through evaluation of powder rheological properties and tablet mechanical properties of directly compressible blends. Aaps Pharmscitech 18 (4), 1177–1189.

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