Novel application of hydroxypropyl methylcellulose to improving direct compaction properties of tablet fillers by co-spray drying

Abstract

This work aimed to investigate the novel application of hydroxypropyl methylcellulose (HPMC) to improving the direct compaction properties of tablet fillers by co-spray drying. Three commonly used types of fillers were investigated. Two representatives were chosen for each type, i.e., (i) water-soluble small molecules: lactose and mannitol; (ii) water-insoluble small molecules: calcium carbonate and anhydrous dibasic calcium phosphate; and (iii) macromolecules: corn starch (practically insoluble in cold water) and chitosan (sparingly soluble in water). Except for chitosan, improvements on both powder properties (e.g., flowability and hygroscopicity) and tableting properties (e.g., tableting ratio, yield pressure, tensile strength, and E_sp) were achieved for the rest five fillers by co-spray drying with a small amount of HPMC. This is mainly attributed to the homogeneous distribution of plastic and nonhygroscopic HPMC macromolecules on the surface of the primary and composite particles. In addition, changes induced by spray drying, such as agglomeration, spheroidization, porosity increase, amorphous formation, and gelatinization, also contribute to some degree to the improvements. The above results, together with the data of lubrication sensitivity and tablet disintegration, show that such a novel application of HPMC is effective and promising.

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1. Introduction

Tablet production by direct powder compaction has increased steadily over the years because it offers economic advantages through its elimination of the granulation step.¹ In general, fillers account for a considerable portion of a tablet formulation. Many commonly used tablet fillers, however, can't be used for direct compaction due to their poor compactibility or/and flowability. To combat this, the problematic fillers are often co-processed with one or more binders. It was reported that the effect of a dry binder depended on the amount added and the particle size of the dry binder. If the amount added is large enough, the surface properties of the core material become identical with those of the pure binder material.² Compared to physical mixing, co-processing the filler with a dissolved binder offers several additional advantages, including uniformity, ease of use, improvement in flowability, and, most importantly, surface-favored distribution of the binder.^3–6 Many co-processing methods can be used, among which spray drying is the most widely used and successful one. A majority of commercially available co-processed excipients are produced by spray drying.^3–6 Co-spray drying uses a one-step continuous process to dry and agglomerate multi-component powders, which reduces the number of unit operations and thus improves production efficiency and reduces costs. The resulting powders are generally homogeneous, subglobular, and porous, with improved physical and mechanical properties, especially of flowability and compactibility. In addition, it is a technique that can be easily automated, scaled up, and equipped for in-line product analysis. These features altogether offer obvious benefits for the development of co-processed excipients.

Among commonly used tablet binders, hydroxypropyl methylcellulose (HPMC) has clear advantages for co-processing. For example, HPMC is much less hygroscopic compared to polyvinylpyrrolidone (PVP) and microcrystalline cellulose (MCC). This not only helped reduce particle adhesion, and thus, improve recovery during spray drying,⁷ but also allowed a high level of HPMC to be used without causing hygroscopic and flowing problems.⁸ In addition, MCC is water insoluble, which necessitated a high MCC level to achieve acceptable uniformity and functional improvements.⁵ In this regard, dissolved HPMC molecules are prone to homogeneous distribution on the surface of the primary and composite particles during co-processing, maximizing their effects and thus allowing a lower level to be used.⁸ As to hydroxypropylcellulose (HPC), the commercially available grade of HPC with the lowest viscosity has much higher viscosity than that of HPMC. The higher the viscosity of a binder is, the severer the adverse effect on tablet disintegration is.

In light of the above, this study aimed to investigate the potential novel application of HPMC E3 (the lowest viscosity grade in the HPMC family) to improving direct compaction properties of tablet fillers by co-spray drying. Commonly used three types of tablet fillers were investigated. Two representatives were chosen for each type, i.e., (i) water-soluble small molecules: lactose and mannitol; (ii) water-insoluble small molecules: calcium carbonate and anhydrous dibasic calcium phosphate; and (iii) macromolecules: corn starch (practically insoluble in cold water) and chitosan (sparingly soluble in water). Powder and tableting properties of each material prepared were characterized. In particular, their tableting behaviours were characterized by a fully instrumented press (Korsch XP1, Germany).

2. Experimental

2.1. Materials

Mannitol (PEARLITOL 50C, E752N, Roquette, France), corn starch (E2310, Roquette, France), calcium carbonate (CC) (14062002, Daheng calcium carbonate Development Co., Ltd, Yidu, China), anhydrous dibasic calcium phosphate (DCPA) (Kede Chemicals Co., Ltd, Lianyungang, China), chitosan (Lichengqu Qianqianxiu chemicals Department, Jinan, China), α-lactose monohydrate (Pharmatose 450M; DFE Pharma, Veghel, Netherlands), hydroxypropyl methylcellulose (HPMC; Methocel E3, Dow Chemical, Midland, MI, USA), cross-linked polyvinylpolypyrrolidone (PVPP; Kollidon CL, BASF, Ludwigshafen, Germany), and magnesium stearate (Sinopharm Chemical Reagent Co., Shanghai, China) were used as supplied. The viscosity of 2% (w/v) aqueous solution of HPMC E3 is 3 mPa s.

2.2. Preparation of filler–HPMC composite particles via spray drying

2.2.1. Preparation of lactose/mannitol–HPMC particles. To minimize the dissolution–precipitation cycle of water-soluble fillers during processing, lactose or mannitol was dispersed homogeneously in its ice-cold saturated water solution containing dissolved HPMC (7.0%, w/w, in the final product) on an ice bath to form the feed dispersion. The solid content of feed dispersions was fixed at 40%. With constant stirring, the feed dispersion was spray-dried immediately using a pilot scale spray dryer (Mobile Minor 2000, Niro, Søborg, Denmark) with a rotary atomizer operated under the following conditions: inlet temperature, 170 °C; outlet temperature, 75 °C; atomizing wheel speed, 20 000 rpm. The dimensions of the drying chamber are 2 m cylindrical height with a diameter of 0.80 m and 60° conical base. The dryer was operated in co-current air flow and allowed to reach the steady state by operating it for at least 30 min with water spraying before the feed was sprayed. The spray dried particles were collected in a reservoir attached to a cyclone and cooled down to room temperature. The particles collected were further dried in a hot-air oven at 60 °C for 3 h and then sealed into plastic bags and stored in desiccators at room temperature until further tests.

2.2.2. Preparation of the rest filler–HPMC particles. The filler was dispersed homogeneously in HPMC water solution (7.0%, w/w, in the final product) on an ice bath to form the feed dispersion. The 9% and 20% solid contents were used for the chitosan and DCPA feed dispersions, respectively, to ensure normal spray drying operation. The rest are the same as those mentioned above.

2.3. Characterization of particles

2.3.1. Moisture content. The moisture content was determined by a fast infrared moisture analyzer (MA35, Sartorius, Germany). About 2 g of each testing sample was dried at 105 °C and the result was recorded until a constant reading was achieved.

2.3.2. Particle size and size distribution. Particle size was determined by laser diffraction (Malvern 2000, Malvern Instruments Ltd, England). The median particle size (D_0.5) was automatically determined while the particle size distribution was represented by span and calculated as follows:where D_0.1, D_0.5, D_0.9 are the diameters of sample at the 10^th, 50^th, and 90^th percentiles of the cumulative percent undersize plot, respectively. Three replicates were carried out for each measurement.

2.3.3. Surface morphology. The morphology of materials was examined under scanning electron microscope (S-3400, Hitachi Ltd, Japan) at an acceleration voltage of 20 kV. Samples were sputter coated (E-1010, Hitachi Ltd, Japan) with gold–palladium and observed at different magnifications.

2.3.4. Flowability. The angle of repose, determined by a powder property tester (Baite Corporation, China), was used to indicate the flowability of the materials. The samples were poured through a vibrating metal funnel onto a platform until a stable and height-fixed heap was formed. The angle of repose was measured as the angle made by the inclined plane of the heap with the horizontal.

2.3.5. Compressibility. The powder property tester was used to determine the bulk (ρ_b) and tapped (ρ_ta) densities for the compressibility studies. The samples were poured through a vibrating metal funnel into a measuring cylinder, which was exactly 100 cm³ and weighed in advance as m₀, until it was full. After the excessive powder was scraped off, the weight of the cylinder was recorded as m₁. The bulk density was calculated by eqn (2).

More samples were poured into the cylinder, which had been combined with a glass sleeve, until an appropriate height. Tapping was carried out for 5 minutes. After the excessive powder was scraped off, the weight of the cylinder was recorded as m₂. The bulk density and Hausner ratio were calculated by eqn (3) and (4), respectively.

2.3.6. Compactibility. Materials were compacted on a fully instrumented press (Korsch XP1, Germany) using 8.5 mm, round flat-faced tooling with a compaction pressure of 123, 176, or 229 MPa. For lubrication, magnesium stearate suspension (0.5%) in acetone was spread on the upper punch, lower punch, and die before compaction. The thickness (T; mm), diameter (D; mm), and crushing force (F; N) of five compacts at each compaction pressure were determined immediately by a crushing force tester (Sotax HT10, Switzerland). The tensile strength (TS) of each compact in MPa was calculated using eqn (5):⁹

The works during compaction were also recorded by the press. The E_sp value was calculated using eqn (6):

where W_net is the net work (J), i.e., the energy that remained after the punch left the compact, and M is the tablet weight (g).

2.3.7. Yield pressure (P_y). The “in-die” method was used. The compaction was carried out as above. The Athy–Heckel eqn (7)¹⁰ was used to analyse the volume reduction mechanism during compaction.where D is the relative density of the compact at pressure P; K is a material constant and is the slope of the linear portion of the plot. P_y is inversely related to the ability of the material to deform plastically under pressure and was calculated from the reciprocal of the slope k by performing linear regression in the compaction phase.

2.3.8. Fast elastic stretch (FES). FES describes the axial elastic recovery in a die and was calculated from the following eqn (8):¹¹where FES is given as a percentage (%), T₁ is the edge thickness of the tablet during unloading, and T₂ represents the edge thickness of the tablet at the time of maximum pressure.

2.3.9. Lubrication sensitivity. Samples of all the co-processed excipients were physically mixed with 0.5% magnesium stearate (w/w) in a 5 L cubic blender for 1, 5, and 10 min, respectively. The mixtures were then compacted as above with a compaction pressure of 123, 176, or 229 MPa. The tensile strength values of the tablets formed were measured as above.

2.3.10. Tablet disintegration. The disintegration time was determined on 6 compacts per sample according to the USP method using a disintegration apparatus (LB-2D, Shanghai Huanghai Ltd, China). Distilled water was used as disintegration medium, which was maintained at 37 °C ± 1 °C. The disintegration time for each compact was recorded separately.

3. Results and discussion

To combat the poor compactibility and flowability of fillers, co-processed excipients based on the combination of a filler with a plastic binder have been developed with some success, such as Cellactose® (75% α-lactose monohydrate–25% powder cellulose), Ludipress® (93.4% α-lactose monohydrate–3.4% crospovidone–3.2% PVP), Microcellac® (75% α-lactose monohydrate–25% MCC), StarLac® (85% α-lactose monohydrate–15% corn starch), Avicel® HFE (90% MCC–10% mannitol), LudiFlash® (90% mannitol–5% Kollidon®–5% polyvinyl acetate),⁵ mannitol–tapioca corn starch,¹² mannitol–chitin (2 : 8),¹³ MCC–calcium carbonate,¹⁴ starch–microcrystalline cellulose,¹⁵ neem gum–rice starch/lactose,¹⁶ maize starch–acacia gum,¹⁷ ethyl methacrylate–tapioca starch,¹⁸ and chitosan–microcrystalline cellulose.¹⁹

However, it is intriguing that HPMC, a commonly used binder in tablets and a common material in film coating, was rarely used for such an application although having suitable properties, such as low hygroscopicity (∼10% equilibrium moisture at 75% relative humidity), high glass transition temperature (170–180 °C), and commercially available grades with low viscosity.²⁰ In a previous report, micronized lactose (∼2 μm) was co-spray dried with HPMC to develop novel lactose-based cushioning agents.⁸ It was found that besides excellent cushioning effects, the products also showed significantly improved compactibility and flowability. However, yet unknown are the effects of HPMC on common grade lactose and other tablet fillers. Therefore, in this study six fillers (three types) were separately co-spray dried with HPMC E3 and the properties of the resulting products were adequately investigated.

3.1 Powder properties (Table 1 and Fig. 1)

The moisture content might markedly influence the powder and tableting properties of excipients. This is especially true for starch.²¹ Therefore, the moisture content of each group material was remained comparable during the study.

In general, the particle sizes of spray-dried products were comparable to, or larger than, those of raw fillers. Co-spray drying with HPMC caused an increase in particle size for water-insoluble anhydrous dibasic calcium phosphate (DCPA), calcium carbonate (CC), and corn starch, but not for water-soluble mannitol and lactose. This might be due to the dissolution–precipitation cycle that water-soluble fillers underwent during processing. No matter how the particle size changed, co-spray drying with HPMC led to a remarkable improvement in flowability for all the six fillers studied. This indicates that changes in shape (from irregular to subglobular) and surface properties (from rough and hygroscopic to smooth and nonhygroscopic) by co-spray drying with HPMC (Fig. 1) are more significantly contributing factors than particle size for flowability improvement. As a whole, the co-spray dried products prepared here can be considered as freely flowing excipients that are capable of being used in the direct compaction process. Moreover, with the use of larger-scale spray driers, products with larger particle sizes, and hence, better flowability would be definitely produced. Therefore, the products developed here are promising at least from the point of view of flowability. In addition, coincided well with a previous report,⁷ co-spray drying with HPMC, via reducing particle adhesion, achieved a higher production yield (81–90%) than spray drying pure fillers alone.

Fig. 1 Scanning electron photomicrographs of (1) the physical mixture of the raw filler ((a) lactose; (b) mannitol; (c) anhydrous dibasic calcium phosphate; (d) calcium carbonate; (e) corn starch; (f) chitosan) and 7% HPMC E3, (2) the co-spray dried product of the raw filler with 7% HPMC E3, and (3) the spray dried product of the pure raw filler (2000×). H represents HPMC E3.

The surface morphology of materials was studied by SEM. Compared to the primary particles, the co-processed composite particles exhibited a significant change in shape and surface topography (Fig. 1). Firstly, the primary particles of the filler and HPMC are no longer distinguishable after co-spray drying (Fig. 1(1) and (2)), indicating that the two raw materials were intimately and homogeneously combined in the composite particles and the surface of the composite particles was covered by HPMC macromolecules. Secondly, unlike irregular and dense particles of fillers, the composite particles, expect for the chitosan-based ones, generally appeared subglobular in shape with plicated surface and increased porosity (Fig. 1(2)). Such structures often indicate good flowability and compactibility. When being spray dried without HPMC, different types of fillers showed different changes (Fig. 1(3)). For water-soluble lactose and mannitol, spheroidization is obvious and the formed composite particles have more smooth and intact surfaces than those obtained by co-spray drying with HPMC (Fig. 1a and b). This should be attributed to the increased viscosity of sprayed droplets by HPMC macromolecules, which reduced the drying velocity and induced the formation and collapse of bubbles at the surface layer of, and within, the drying composite particles. For water-insoluble DCPA and CC, no observable changes happened when they were spray dried alone (Fig. 1c and d). That is to say, the effect of HPMC on particle morphology is more significant for this type of filler than for water-soluble fillers. When corn starch was spray dried alone, agglomeration of the primary particles also happened just as it was spray dried with HPMC, although less in extent (Fig. 1e). This indicates that gelatinization of corn starch happened to some extent during spray drying. The gelatinized corn starch acted as a binder, causing the agglomeration. As to chitosan, there are no observable differences between the products prepared by spray drying alone and with HPMC, respectively (Fig. 1f).

3.2. Tableting properties

3.2.1. Compactibility. Tableting parameters, including tableting ratio, fast elastic stretch, yield pressure, and porosity, for the excipients studied were recorded and are summarized in Table 2. Tableting ratio describes the deformation behaviour of a material in the tableting process. The smaller the value, the better the compressibility and compactibility of the material. As shown in Table 2, for all the six groups of excipients, the tableting ratio for the co-processed excipient was lower than those for the raw filler, its spray-dried product, and its physical mixture with HPMC.

Table 1 Powder properties of the materials studied in this work (n = 3)^a

Composition	Processing way	AR (°)	ρb (g cm^−3)	ρta (g cm^−3)	HR	D0.5 (μm)	Span	MC (%)	PY (%)
a AR, angle of repose; ρb, bulk density; ρta, tapped density; HR, Hausner ratio; D0.5, the median particle size; MC, moisture content; PY, percent yield; PM, the physical mixture of the raw filler with HPMC; SD, the spray-dried raw filler; co-SD, the co-spray dried product of the raw filler and HPMC; co-SD + PVPP, the physical mixture of co-SD and 3.5% PVPP; DCPA, anhydrous dibasic calcium phosphate; CC, calcium carbonate.b Standard deviation.
Mannitol–7% HPMC	Co-SD	34.6 (0.7)^b	0.362 (0.002)	0.540 (0.001)	1.49 (0.01)	22.14 (0.20)	2.12 (0.14)	0.70 (0.16)	89.91
	Co-SD + PVPP	34.1 (0.6)	0.361 (0.002)	0.541 (0.001)	1.49 (0.01)	22.18 (0.21)	2.13 (0.12)	0.64 (0.13)	—
	SD	39.1 (1.1)	0.517 (0.001)	0.752 (0.001)	1.45 (0.02)	13.21 (0.31)	2.87 (0.16)	0.69 (0.15)	81.22
	PM	54.1 (0.8)	0.443 (0.001)	0.741 (0.002)	1.67 (0.01)	23.31 (0.31)	2.28 (0.18)	0.72 (0.12)	—
	Raw mannitol	54.3 (0.8)	0.446 (0.001)	0.745 (0.002)	1.67 (0.03)	23.40 (0.33)	2.29 (0.17)	0.58 (0.11)	—
Lactose–7% HPMC	Co-SD	39.5 (0.4)	0.331 (0.002)	0.502 (0.002)	1.52 (0.01)	22.33 (0.29)	1.94 (0.11)	4.24 (0.11)	84.43
	Co-SD + PVPP	39.1 (0.6)	0.332 (0.002)	0.501 (0.001)	1.51 (0.01)	22.35 (0.31)	1.92 (0.13)	4.24 (0.12)	—
	SD	51.6 (0.5)	0.395 (0.001)	0.771 (0.001)	1.95 (0.02)	21.01 (0.31)	2.14 (0.22)	3.96 (0.13)	75.12
	PM	55.1 (0.8)	0.443 (0.001)	0.784 (0.001)	1.77 (0.01)	21.31 (0.33)	2.25 (0.14)	2.85 (0.12)	—
	Raw lactose	55.3 (0.8)	0.456 (0.001)	0.795 (0.002)	1.74 (0.03)	21.03 (0.32)	2.23 (0.21)	2.69 (0.12)	—
DCPA–7% HPMC	Co-SD	37.5 (0.5)	0.624 (0.002)	0.935 (0.004)	1.50 (0.02)	30.56 (0.34)	1.82 (0.22)	0.34 (0.13)	83.11
	Co-SD + PVPP	37.6 (0.7)	0.621 (0.003)	0.931 (0.003)	1.49 (0.03)	30.54 (0.33)	1.81 (0.11)	0.32 (0.12)	—
	SD	52.6 (0.5)	0.908 (0.002)	1.628 (0001)	1.79 (0.01)	19.86 (0.33)	2.24 (0.25)	0.29 (0.12)	79.14
	PM	52.5 (0.3)	0.843 (0.002)	1.687 (0.001)	2.01 (0.02)	22.95 (0.31)	2.37 (0.11)	0.33 (0.21)	—
	Raw DCPA	52.7 (0.2)	0.848 (0.001)	1.691 (0.002)	1.99 (0.01)	22.99 (0.32)	2.36 (0.20)	0.34 (0.12)	—
CC–7% HPMC	Co-SD	37.8 (0.6)	0.429 (0.002)	0.667 (0.001)	1.56 (0.001)	29.88 (0.31)	1.88 (0.12)	0.44 (0.13)	81.25
	Co-SD + PVPP	37.6 (0.6)	0.428 (0.002)	0.667 (0.001)	1.56 (0.01)	29.86 (0.22)	1.87 (0.13)	0.43 (0.11)	—
	SD	51.5 (0.5)	0.982 (0.003)	1.651 (0.002)	1.68 (0.02)	18.69 (0.24)	1.52 (0.12)	0.39 (0.11)	78.27
	PM	53.9 (0.5)	0.923 (0.001)	1.525 (0.002)	1.64 (0.01)	17.44 (0.25)	1.59 (0.11)	0.47 (0.12)	—
	Raw CC	54.2 (0.7)	0.929 (0.001)	1.529 (0.002)	1.65 (0.02)	17.45 (0.26)	1.59 (0.12)	0.48 (0.11)	—
Starch–7% HPMC	Co-SD	46.8 (0.7)	0.378 (0.002)	0.576 (0.001)	1.52 (0.001)	31.59 (0.34)	1.72 (0.21)	8.16 (0.14)	81.25
	Co-SD + PVPP	46.5 (0.5)	0.375 (0.001)	0.574 (0.002)	1.54 (0.001)	31.58 (0.31)	1.71 (0.23)	8.53 (0.21)	—
	SD	45.6 (0.5)	0.516 (0.002)	0.771 (0.001)	1.49 (0.002)	13.55 (0.22)	0.93 (0.22)	8.26 (0.22)	60.21
	PM	48.2 (0.6)	0.478 (0.001)	0.835 (0.002)	1.75 (0.002)	13.12 (0.22)	0.83 (0.11)	8.43 (0.24)	—
	Raw starch	48.3 (0.6)	0.486 (0.001)	0.840 (0.002)	1.73 (0.002)	13.15 (0.34)	0.84 (0.12)	8.23 (0.12)	—
Chitosan–7% HPMC	Co-SD	35.5 (0.5)	0.302 (0.001)	0.485 (0.001)	1.60 (0.01)	50.98 (0.31)	2.28 (0.23)	3.56 (0.14)	88.70
	Co-SD + PVPP	35.6 (0.8)	0.301 (0.002)	0.479 (0.001)	1.59 (0.01)	50.94 (0.21)	2.28 (0.11)	3.57 (0.23)	—
	SD	38.5 (0.6)	0.361 (0.002)	0.549 (0.003)	1.52 (0.02)	60.64 (0.32)	2.35 (0.21)	5.04 (0.21)	86.54
	PM	50.9 (0.5)	0.332 (0.003)	0.631 (0.002)	1.89 (0.01)	57.40 (0.21)	2.43 (0.13)	4.21 (0.42)	—
	Raw chitosan	49.5 (0.6)	0.338 (0.002)	0.630 (0.002)	1.86 (0.02)	57.41 (0.22)	2.41 (0.31)	4.24 (0.34)	—

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Table 2 Tableting parameters of the materials studied in this work (n = 3)^a

Composition	Processing way	TR (%)	Py^c (MPa)	FES (%)	PL (%)	PuL (%)	PuL − PL (%)
a TR, tableting ratio; FES, fast elastic stretch; Py, yield pressure; PL, porosity loaded; PuL, porosity unloaded; PM, the physical mixture of the raw filler and HPMC; SD, the spray-dried raw filler; co-SD, the co-spray dried product of the raw filler with HPMC; co-SD + PVPP, the physical mixture of co-SD and 3.5% PVPP; DCPA, anhydrous dibasic calcium phosphate; CC, calcium carbonate.b Standard deviation.c The yield pressure was determined under the compaction force range of 60–120 MPa.
Mannitol–7% HPMC	Co-SD	18.93 (0.09)^b	175.22 (0.80)	7.63 (0.23)	12.36 (0.44)	18.66 (0.47)	6.30 (0.44)
	Co-SD + PVPP	18.20 (0.01)	170.92 (0.68)	7.74 (0.16)	11.40 (0.48)	18.00 (0.36)	6.60 (0.36)
	SD	21.18 (0.34)	196.11 (0.59)	7.83 (0.10)	11.73 (0.60)	18.19 (0.43)	6.46 (0.43)
	PM	19.11 (0.10)	203.88 (0.61)	8.11 (0.14)	10.65 (0.01)	17.17 (0.27)	6.51 (0.27)
	Raw mannitol	19.39 (0.01)	232.67 (0.33)	7.43 (0.34)	11.16 (0.12)	17.49 (0.32)	6.33 (0.12)
Lactose–7% HPMC	Co-SD	14.95 (0.01)	167.42 (0.17)	7.07 (0.11)	17.62 (0.18)	23.43 (0.30)	5.81 (0.18)
	Co-SD + PVPP	14.91 (0.03)	155.07 (0.83)	7.46 (0.01)	16.81 (0.13)	22.58 (0.37)	5.77 (0.13)
	SD	15.86 (0.11)	210.79 (0.12)	8.32 (0.29)	13.80 (0.12)	19.42 (0.02)	5.61 (0.12)
	PM	17.73 (0.20)	253.89 (0.20)	8.04 (0.01)	15.81 (0.36)	22.47 (0.34)	6.66 (0.34)
	Raw lactose	17.47 (0.11)	331.63 (0.11)	8.40 (0.40)	14.98 (0.09)	21.62 (0.12)	6.64 (0.12)
DCPA–7% HPMC	Co-SD	19.25 (0.04)	373.24 (0.89)	6.97 (0.46)	25.75 (0.31)	30.59 (0.01)	4.84 (0.31)
	Co-SD + PVPP	19.37 (0.12)	375.60 (1.17)	7.84 (0.40)	25.90 (0.66)	31.29 (0.37)	5.39 (0.37)
	SD	25.22 (0.16)	482.59 (0.73)	7.33 (0.64)	26.32 (0.64)	31.36 (0.16)	5.04 (0.13)
	PM	21.85 (0.04)	486.91 (0.95)	7.90 (0.11)	27.28 (0.39)	32.60 (0.38)	5.32 (0.38)
	Raw DCPA	25.01 (0.13)	506.70 (1.44)	6.63 (0.15)	24.35 (0.14)	29.02 (0.10)	4.67 (0.10)
CC–7% HPMC	Co-SD	15.60 (0.27)	313.58 (0.76)	8.53 (0.12)	25.48 (0.18)	31.06 (0.67)	5.58 (0.18)
	Co-SD + PVPP	15.52 (0.06)	312.36 (0.88)	9.14 (0.24)	26.20 (0.31)	32.15 (0.48)	5.95 (0.48)
	SD	23.30 (0.33)	385.31 (0.71)	8.48 (0.34)	25.68 (0.42)	31.23 (0.55)	5.55 (0.42)
	PM	21.20 (0.01)	388.85 (0.93)	8.29 (0.25)	26.84 (0.26)	32.44 (0.17)	5.61 (0.17)
	Raw CC	20.25 (0.26)	399.28 (0.13)	9.79 (0.16)	23.75 (0.34)	30.77 (0.60)	7.01 (0.34)
Starch–7% HPMC	Co-SD	17.00 (0.20)	103.85 (0.62)	12.40 (0.16)	6.26 (0.68)	16.60 (0.54)	10.34 (0.54)
	Co-SD + PVPP	17.09 (0.06)	104.46 (0.42)	11.65 (0.14)	6.94 (0.22)	16.71 (0.30)	9.77 (0.22)
	SD	23.51 (0.20)	119.15 (1.21)	12.97 (0.08)	5.34 (0.55)	16.21 (0.44)	10.87 (0.44)
	PM	18.49 (0.03)	132.71 (1.04)	11.94 (0.30)	8.21 (0.24)	17.75 (0.48)	9.55 (0.24)
	Raw starch	18.14 (0.09)	135.30 (0.33)	12.58 (0.13)	7.63 (0.45)	18.14 (0.07)	10.51 (0.45)
Chitosan–7% HPMC	Co-SD	15.52 (0.07)	110.58 (0.36)	14.25 (0.21)	3.75 (0.75)	15.74 (0.27)	12.00 (0.27)
	Co-SD + PVPP	15.51 (0.07)	106.15 (0.98)	13.92 (0.11)	3.67 (0.15)	15.44 (0.09)	11.77 (0.15)
	SD	18.41 (0.32)	112.35 (0.33)	14.31 (0.23)	2.68 (0.68)	15.31 (0.23)	12.63 (0.23)
	PM	15.87 (0.03)	131.96 (0.82)	14.68 (0.16)	4.54 (0.29)	16.65 (0.47)	12.11 (0.29)
	Raw chitosan	15.87 (0.01)	136.09 (0.46)	14.88 (0.06)	4.33 (0.51)	16.72 (0.43)	12.39 (0.43)

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Yield pressure (P_y) is another parameter related to the ability of a material to deform under pressures.^22,23 Typically, lower values of P_y indicate the onset of deformation at lower applied pressures. A low P_y value is an essential characteristic for a material to act as an excellent tableting excipient. In this study, linear correlations of all the Athy–Heckel plots were accurate over the compaction pressure range of 60–120 MPa with correlation coefficients between 0.9951 and 0.9990. As a whole, the data of P_y are well coincided with those of tableting ratio, also clearly indicating that the compactibility of the fillers was improved by co-spray drying with HPMC. This is attributed to the plastic deformation nature of HPMC. In general, amorphous materials have a tendency to plastic deformation and crystalline to brittle fracture. For polymers, even if having a high crystalline portion, they may also tend to plastic deformation facilitated by the presence of slip planes, dislocations, and the nano-sized individual microcrystals. For example, the plastic behaviour of MCC has been deduced from plenty of studies.²⁴ Compared to MCC, HPMC E3 is also a cellulose derivative, but an amorphous polymer.⁸ During compaction, entangled flexible HPMC macromolecules tend to permanent deformation by nonspecific plastic flow. At some contact areas among, and within, particles, temperatures might be higher than the glass transition temperature of HPMC E3. The transition from the glass state to the rubber state further facilitates the plastic flow.

In addition, different types of fillers exhibited some differences in P_y reduction. For water-soluble mannitol and lactose, spray drying without HPMC has already led to significant reductions in their P_y values by 16% and 36%, respectively. Co-spray drying with HPMC caused further reductions in P_y by 11% and 20%, compared to spray-dried mannitol and lactose, respectively. For water-insoluble DCPA and CC, the effect of spray drying without HPMC on P_y was negligible. Only approximately 4% reductions were observed. In comparison, co-spray drying with HPMC reduced both of the P_y values of DCPA and CC by approximately 24%. Since corn starch and chitosan are macromolecules and plastic in nature, they themselves have significantly lower P_y values than the other two types of fillers. Spray drying without HPMC reduced their P_y values by 12% and 18%, respectively. However, co-spray drying with HPMC caused different further changes for the two macromolecules, i.e., a 13% further reduction for corn starch and nearly no change for chitosan. This abnormal phenomenon for chitosan might be due to a specific interaction between chitosan and HPMC molecules and might also be related to the abnormal tensile strength versus tableting pressure profiles for chitosan-based excipients (Fig. 2f). As to the parameters of fast elastic stretch and porosity, no clear trends were observed for all the six groups, suggesting that the effect of HPMC on them might be insignificant.

Fig. 2 Tensile strength profiles for the raw material (RM) ((a) lactose; (b) mannitol; (c) anhydrous dibasic calcium phosphate; (d) calcium carbonate; (e) corn starch; (f) chitosan), its co-processed product with 7% HPMC E3, and the other relevant materials. PM, the physical mixture of the raw material and HPMC; SD, the spray-dried raw material; co-SD, the co-spray dried product of raw material and HPMC; co-SD + PVPP, the physical mixture of co-SD and 3.5% PVPP (n = 3).

Molecular interactions between the filler and HPMC also vary with the type of the filler. For water-soluble mannitol and lactose, their dissolved molecules co-precipitated with HPMC molecules during drying to form amorphous solid dispersion. The intimate molecular interactions facilitate the stability of amorphous parts of the fillers, which also contribute to some degree to the improved compactibility of their co-processed excipients. For water-insoluble DCPA and CC, there should be no prominent intermolecular interactions between the filler and HPMC molecules. Instead, HPMC molecules precipitated on the filler particles and bound them together to form the composite secondary particles. The case for chitosan should be similar to that for water-insoluble fillers except more intimate interface interactions. However, intimate molecular interactions might happen between molecules of gelatinized corn starch and HPMC, resulting in the formation of a combined binder layer on the primary and composite particles.

To further evaluate the compactibility, tensile strength profiles for the six groups of excipients were constructed over the tableting pressure range of 123–229 MPa (Fig. 2). A high tensile strength is related to a large area of bond formation, which is associated with the surface area.²⁵ Some common trends are observed in the study. Firstly, the profiles for the physical mixtures are either overlapped with, or just slightly higher than, those for the raw fillers, indicating that the effects of physically-mixed 7% HPMC on the compactibility of all the six fillers are insignificant. Secondly, the profiles for the co-spray dried products are markedly higher than those for the physical mixtures (4.20 to 6.28, 1.63 to 4.12, 1.81 to 2.69, 1.34 to 1.63, and 1.05 to 1.24 times higher for the CC, lactose, corn starch, mannitol, and DCPA groups, respectively), with the exception of the chitosan group (1.02 to 1.11 times lower rather than higher for this group). These results, together with those previously reported,^26–28 clearly suggest the importance of the specific distribution form of HPMC (homogeneous distribution on the surface of the primary and composite particles) achieved by the co-spray drying process. Thirdly, both the formation of a small portion of amorphous mannitol and lactose and the partial gelatinization of corn starch also contribute to some degree to the compactibility improvement of raw materials.^29–31 Lastly, the addition of the superdisintegrant PVPP has no remarkable influence on the compactibility of the co-spray dried products.

The E_sp values, which represent the energy retained in the tablet after unloading and are related to the deformation properties of tested materials as well as their binding properties, were calculated based on the works recorded by the press. In general, except for the chitosan group, the trends of the E_sp curves are similar to those of tensile strength (Fig. 2 and 3). A higher E_sp value means that a larger part of the energy input was utilized in irreversible deformation of the tableted material, and thus, a tablet with higher tensile strength would be made. The abnormity for the chitosan group indicates that spray drying, on the one hand, improved the flowability of the material, thus reducing the friction and increasing the net work during tableting; on the other hand, it must induce certain changes in surface properties of chitosan particles, resulting in a considerable reduction in binding ability between particles. Moreover, co-spray drying with HPMC appears to further aggravate, rather than mitigate, the reduction.

Fig. 3 E_sp profiles for the raw material (RM) ((a), lactose; (b) mannitol; (c) anhydrous dibasic calcium phosphate; (d) calcium carbonate; (e) corn starch; (f) chitosan), its co-processed product with 7% HPMC E3, and the other relevant materials. PM, the physical mixture of the raw material and HPMC; SD, the spray-dried raw material; co-SD, the co-spray dried product of raw material and HPMC; co-SD + PVPP, the physical mixture of co-SD and 3.5% PVPP (n = 3).

3.2.2. Lubrication sensitivity. During the mixing of tablet ingredients with magnesium stearate, the latter is distributed over the ingredients, either as a surface film or as a free fraction. The deteriorating effect of magnesium stearate on the mechanical strength of tablets has been widely investigated.^32–34 The results show that materials that compact predominantly by fragmentation are little sensitive to the addition of lubricants while materials that behave plastically show a considerable loss in their capacity to form links.

In this study, the tablet tensile strength versus lubricant mixing time curves were constructed over the tableting pressure range of 123–229 MPa (Fig. 4) to evaluate the lubrication sensitivity of co-spray dried products. It was found that both the plastic corn starch- and chitosan-based co-processed products showed some lubrication sensitivity. After they were mixed with 0.5% magnesium stearate for 10 min, the tensile strengths of tablets they formed reduced by 21% and 15%, respectively. Lactose, mannitol, DCPA, and CC are all crystal materials, having some brittleness, and thus, undergoing some fragmentation during tableting. This, together with large specific surface areas and high porosity of co-spray dried products, effectively offset the adverse effect that magnesium stearate brought in. As a result, no obvious lubrication sensitivity was observed for the products based on them.

Fig. 4 Tensile strength versus lubricant mixing time curves for tablets made at three pressures from the mixture of 0.5% magnesium stearate (MS) and 99.5% the co-spray dried product of HPMC E3 with the filler ((a) lactose; (b) mannitol; (c) anhydrous dibasic calcium phosphate; (d) calcium carbonate; (e) starch; (f) chitosan) (n = 3). : mixing without MS; : mixing with MS for 1 minute; : mixing with MS for 5 minutes; : mixing with MS for 10 minutes.

3.2.3. Tablet disintegration. Tablet disintegration is another important property needed to be considered when developing a new tablet excipient. The compactibility of an excipient is often improved at the expense of its disintegration ability. The disintegration times of tablets with crushing forces of 60–140 N formed by the lactose, mannitol, CC, DCPA, and corn starch based co-processed excipients were 10–11 min, 6.5–8.5 min, 18–25 min, >2 h, and 9–12 min, respectively. The external addition of 3.5% PVPP to these co-processed excipients before tableting reduced the disintegration times of tablets to 7–8 min, 0.25–1.65 min, 8–12 min, 30–51 s, and 5–7 min, respectively, all of which are less than the 15 min requirement for rapid release tablets in the European pharmacopoeia. In addition, no remarkable influences on the compactibility were observed by the addition of PVPP (Fig. 2). Therefore, disintegration appears not to be a limiting factor for the application of the co-processed excipients developed here.

4. Conclusions

The feasibility of improving the powder and tableting properties of commonly used three types of fillers and making them suitable for use in direct powder tableting process by co-spray drying with a small amount of dissolved HPMC was determined in the study. Except for chitosan, improvements on both powder properties (e.g., flowability and hygroscopicity) and tableting properties (e.g., tableting ratio, yield pressure, tensile strength, and E_sp) were achieved for the rest five fillers by co-spray drying with HPMC. This is mainly attributed to the homogeneous distribution of plastic and nonhygroscopic HPMC molecules on the surface of the primary and composite particles. In addition, changes induced by spray drying, such as agglomeration, spheroidization, porosity increase, amorphous formation, and gelatinization, are also attributed to some degree to the improvements. The above results, together with the data of lubrication sensitivity and tablet disintegration, show that the potential novel application of HPMC to improving the direct compaction properties of tablet fillers by co-spray drying is effective and promising.

Conflict of interest

The authors report no conflicts of interest.

Acknowledgements

This work was supported by the Innovation Program of Shanghai Municipal Education Commission (13ZZ098); the funds from Shanghai Municipal Commission of Health and Family Planning (ZY3-CCCX-3-5001) and Science and Technology Commission of Shanghai Municipality (15DZ2292000); the Science and Technology Development Fund of Pudong New Area (PKF-2013-003); and the natural science fund within budget of Shanghai university of traditional Chinese medicine (2013JW27).

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