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Disintegrant Selection in Hydrophobic Tablet Formulations

Published:November 09, 2020DOI:https://doi.org/10.1016/j.xphs.2020.11.002

      Abstract

      The hydrophobicity of poorly soluble drugs can delay tablets disintegration. We probed here the influence of different disintegrants on the disintegration of challenging hydrophobic formulations. Tablets containing diluents, hydrogenated vegetable oil and either sodium starch glycolate (SSG), croscarmellose sodium (CCS) or crospovidone (XPVP) were prepared. The disintegration time of tablets was tested immediately and after storage at 40 °C and 75% RH in sealed bags. Results show that storage and compression force had a negative effect on disintegration, particularly with 1% disintegrant. The performance of the three disintegrants was in the following order: CCS (best) > SSG > XPVP. For example, tablets containing 1% CCS, SSG and XPVP, compressed at 20 kN, disintegrated in ≈3, ≈12 and ≈69 min, respectively, after two months storage. Settling volume, liquid uptake and effect of storage on physical properties of the pure disintegrants were also studied and revealed that the reduced performance of XPVP is related to: 1) its rapid, yet short-range expansion upon liquid exposure and 2) its change of behaviour on storage. In conclusion, CCS ensured rapid disintegration at low concentration across various compression forces and storage times. Thus, the use of CCS in hydrophobic tablet formulations is recommended.

      1. Introduction

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      leading to changes on storage. It is intuitive that the “pre-activation” of the disintegrant swelling due to absorbed moisture can be deleterious to the disintegrant performance. Moreover, all other formulation components can contribute to hardening or softening of the tablets during storage, both of which could influence disintegration. Hersen-Delesalle et al. studied the effect of composition and relative humidity on the mechanical properties of pharmaceutical tablets made of ternary mixtures of diluents, disintegrants and lubricant. At high relative humidity, tablets showed a significant reduction in tensile strength. This drop in mechanical properties was more evident for XPVP, than CCS and SSG. Accordingly, SEM images of lactose tablets containing disintegrants and stored for 2 weeks at 50% relative humidity (RH) revealed the presence of micro-cracks, that were wider when XPVP was used.
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      are less prone to humidity effects. Different results were obtained by Quodbach and Kleinebudde, who also prepared tablets of DCP and disintegrants and studied the effect of RH on disintegration. Upon 2 weeks exposure to conditions ranging between 5% and 80% RH, the disintegration performance of polacrilin potassium, XPVP and CCS were not significantly affected; on the contrary, the disintegration times of tablets containing SSG declined at higher RH conditions.
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      However, information on the effect of storage on the performance of superdisintegrants in hydrophobic formulations are scarce. We address this gap of knowledge in our work. Here, we developed a model formulation containing diluents, 10% solid hydrogenated vegetable oil (HVO), as the hydrophobic component,
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      and 1 or 4% of either SSG, CCS and XPVP, as disintegrants. Freshly prepared tablets were tested for their disintegration times in water, HCl at pH 1, and phosphate buffer at pH 6.8. Tablets were also stored in sealed bags at 40 °C and 75% RH and disintegration studies repeated after 1, 7, 14, 28 and 56 days. Moreover, to interpret the obtained results, liquid uptake and swelling volume of pure disintegrants were studied. Finally, to understand the effect of storage on the action of disintegrants devoid of any other formulation factor, we also monitored changes of physical characteristics [hardness, thickness, diameter and loss on drying (LOD)] of pure disintegrant tablets upon storage.

      Materials and Methods

       Materials

      Dibasic calcium phosphate dihydrate (DCP, Emcompress®, JRS Pharma, Germany) and microcrystalline cellulose (MCC, Vivapur®, JRS Pharma, Germany) were used as insoluble fillers. Hydrogenated vegetable oil (HVO, Lubritab®, JRS Pharma, Germany – particle size: d50 ≈ 110 μm and d90 ≈ 190 μm) and sodium stearyl fumarate (SSF, Pruv®, JRS Pharma, Germany) served as hydrophobic model compound and lubricant, respectively. As disintegrants, sodium starch glycolate (SSG, Explotab®, JRS Pharma, Germany), croscarmellose sodium (CCS, Vivasol ®, JRS Pharma, Germany) and crospovidone (XPVP, Vivapharm® PVPP XL, JRS Pharma, Germany) were used. Furthermore, hydrochloric acid, potassium dihydrogenphosphate and sodium hydrogenphosphate dihydrate (Emsure®, Merck, Germany) were used for the preparation of the media.

       Methods

       Settling Volume of Pure Disintegrants

      1 g of either SSG, CCS or XPVP was weighed into a 150 mL beaker and was mixed with 70 mL of distilled water, phosphate buffer (PB) pH 6.8 or 0.1 M HCl. The suspension was stirred with a glass rod to disperse lumps and then transferred into a 100 mL graduated glass cylinder. The walls of this cylinder were rinsed with fresh media and the volume brought to 100 mL. This mixture was left standing for 2 h, then the settling volume (i.e. the volume of the sediment) was determined.

       Liquid Uptake of Pure Disintegrants

      A 250 mL beaker filled with 200 mL of either distilled water, 0.1 M HCl or PB pH 6.8 was placed on a Sartorius M-Prove balance (Sartorius, Germany). The balance was connected to a computer equipped with a custom-made software that recorded the balance values every second. 5 g of either SSG, CCS or XPVP were weighed into a fritted sleeve which contained a porosity 0 frit with an inner diameter of 3 cm on one end (Carl Roth, Germany). The fritted sleeve was immersed into the glass beaker with the bottom of the sleeve at the same height as the 150 mL mark on the beaker. The weight gain due to liquid uptake through the powder was recorded for 10 min.

       Tablets Preparation

      Table 1 shows the compositions of the tablet formulations. Powder mixtures of the hydrophobic formulations were blended in a freefall blender (Brunimat Type Porta, Brunimatec Suisse, Switzerland) for 15 min. After addition of sodium stearyl fumarate, the powder was mixed for further 3 min. The blends were then compressed into 500 mg flat tablets of 13 mm of diameter, using a 13-station Pressima rotary tablet press (Pressima 13 EU-D, IMA Kilian, Germany) at a compression speed of 10 rpm. For each formulation, tablets were made at 5, 10, 15 and 20 kN of compression force.
      Table 1Compositions and Abbreviations of the Formulations.
      AbbreviationComponents (% w/w)
      Diluent/binderDisintegrantsHydrophobic compoundLubricant
      DCPMCCSSGCCSXPVPHVOSSF
      Hydrophobic formulationsw/o6821101
      1% SSG68201101
      1% CCS68201101
      1% XPVP68201101
      4% SSG68174101
      4% CCS68174101
      4% XPVP68174101
      Pure disint.SSG100
      CCS100
      XPVP100
      400 mg tablets made of pure disintegrants were also prepared at a compression force of 30 kN.

       Tablets Storage

      Pure disintegrants tablets (Table 1) were stored for 1, 7, 14 and 28 days at either 1) room conditions [21.5 ± 1.5 °C, 50% ± 10%RH, inside heat-sealed multilayer laminate bags; composition: PET-Alu-PE (19, 15 and 100 μm, respectively)], or 2) in a Memmert HCP 246 (Memmert, Germany) cabinet set at 40 °C and 75% RH on an open tray, or 3) inside the sealed bags in the cabinet set at 40 °C and 75% RH.
      Hydrophobic tablets (Table 1) were stored for 1, 7, 14, 28 and 56 days in the sealed bags in the chamber set at 40 °C and 75% RH. This condition simulates storage of tablets inside blisters (the sealed bags have similar composition to alu-alu blister foils), exposed to high temperature and humidity conditions.

       Physical Characterisation of Pure Disintegrant Tablets

      Tablets' hardness, thickness, diameter, loss on drying (LOD) and ability to expand upon exposure to fluids were evaluated for pure disintegrant tablets before (time 0) and after storage. Measurements at time 0 were taken within 2 h from compression. Tablets’ hardness was analysed using a hardness tester (Ewerka TBH 250 TD, Germany). Tablet diameter and thickness were measured by the hardness tester or with a calliper (Traceable® digital calliper, VWR International, USA). Ten tablets were tested. For the LOD, 10 tablets were crushed in a mortar and pestle and the LOD of 2–3 g of the resulting powder was measured using a moisture analyser (Ohaus MB 45, USA).
      To test the ability of the disintegrants to expand upon exposure to fluids, tablets were wetted by 6 drops of water using a plastic dropper. Morphological changes of the tablet were visualised by taking pictures of the tablets prior, and after, exposure to the water drops.

       Disintegration Test

      Disintegration tests were conducted on hydrophobic tablets, freshly prepared (i.e. time 0) and after storage. Disintegration time of six tablets per batch was determined using a disintegration apparatus (Sotax DT2, Switzerland) with automated detection of disintegration end-point. Tests were performed in 900 mL of either water, 0.1 M HCl (pH 1) or PB (pH 6.8) at a temperature of 37.0 ± 2 °C.

      Results and Discussion

       Understanding the Performance of Pure Disintegrants

      Prior to testing the disintegration of the model hydrophobic tablets, we determined the settling volume, liquid uptake, as well as the effect of storage on the physical characteristics of the disintegrants alone, devoid of other confounding formulation factors.

       Water Uptake and Settling Volume of Pure Disintegrants

      The settling volume of SSG, CCS and XPVP in water, 0.1 M HCl and PB pH 6.8 are reported in Fig. 1. In each media, the settling volume ranked in this order: SSG > CCS > XPVP. The type of media influenced the swelling volume of SSG and CCS, with the highest values obtained in water and PB and the lowest obtained in HCl. The settling volume of XPVP was always lower than that of other disintegrants and it remained less affected by the type of media.
      Figure thumbnail gr1
      Fig. 1Settling volume (mean ± SD, n = 3) of the three disintegrants in different media. The SD is virtually zero when the same volume (in mL) was measured for the replicates.
      Settling volume, also called swelling volume or bulk swelling,
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      is a measure of the volume of hydration of the particles of the disintegrant. SSG swelled more than the other two disintegrants, as a result of a greater hydration of the polymer chains, which develops in the three dimensions.
      • Rojas J.
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      Functional assessment of four types of disintegrants and their effect on the spironolactone release properties.
      Although they have a similar chemical structure, CCS swelled less than SSG, due to a preferential two-dimensional hydration of the CCS fibre particles that do not swell much through their length.
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      Functional assessment of four types of disintegrants and their effect on the spironolactone release properties.
      XPVP, which is known to swell minimally, had the lowest values of settling volume.
      • Zhao N.
      • Augsburger L.L.
      The influence of swelling capacity of superdisintegrants in different pH media on the dissolution of hydrochlorothiazide from directly compressed tablets.
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      • Ruge V.
      Functional assessment of four types of disintegrants and their effect on the spironolactone release properties.
      The greater swelling volume of SSG and CCS in water and PB compared to HCl is due to the ionisation of the polymer carboxylic acid groups at neutral pH, resulting in repulsion and disentanglement of the hydrating polymer chain. XPVP, being non-ionisable,
      • Quodbach J.
      • Kleinebudde P.
      A critical review on tablet disintegration.
      was seldom affected by the medium pH.
      The dynamics of liquid sorption of SSG, CCS and XPVP are reported in Fig. 2a–c, respectively. The kinetics of liquid uptake greatly differ between XPVP and the other two disintegrants: XPVP shows a rapid uptake of liquid within the first 90 s, followed by a plateau, thereafter. SSG and CCS have a more gradual and continuous liquid sorption. For all three disintegrants the medium pH did not affect the sorption profiles, although SSG showed a greater liquid uptake in water compared to HCl and PB. On the contrary, CCS absorbed water more slowly, compared to HCl and PB.
      Figure thumbnail gr2
      Fig. 2Liquid uptake of SSG (a), CCS (b) and XPVP (c) powder in different media. The shading in the background represents the SD (n = 3).
      Interestingly, both in the case of SSG and CCS, the swelling volume upon exposure to fluids for 2 h (Fig. 1) was greater in PB than HCl, due to the ionisation of the anionic polymers at the more neutral pH, yet the initial liquid sorption (Fig. 2a and b) was nearly superimposable for the two media. This difference between the results is related to the different properties that each technique measures. While settling volume is purely a measure of the maximum volume of hydration of the polymer chains as a bulk, the liquid sorption is a result of both hydration (swelling) and wicking of the liquid between the powder particles.
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      We reason that SSG and CCS hydrate and swell more in PB (Fig. 1), yet the polymer swelling closes-up the air voids between particles through which wicking could occur, thus hindering the capillary transport of liquid. In HCl, the unionised polymers swell less (Fig. 1), maintaining the gaps and channels between particles open for the capillary sorption of media through the hydrophilic polymer particles, ultimately resulting in efficient liquid uptake. Thus, the gravimetric liquid sorption of SSG and CCS powders (Fig. 2a and b) is more swelling-driven in PB and more wicking-driven in HCl. As both swelling and wicking promote disintegration,
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      • Kleinebudde P.
      A critical review on tablet disintegration.
      SSG and CCS are expected to perform well in both media. A comparison between the two swelling disintegrants reveals that although CCS had lower settling volume (i.e. swelling- Fig. 1) than SSG both in HCl and PB, CCS sorbs as much liquid as SSG (Fig. 2). This indicates that the media uptake of CCS is more driven by wicking than swelling compared to SSG.
      The kinetic of water sorption should also be considered: SSG and CCS take-up liquid slowly, possibly reflecting a slow kinetic of disentanglement and hydration of polymer chains. XPVP, which shows only minimal settling volume, seems to absorb the liquid rapidly (Fig. 2c), without being hindered by the swelling. Thus, in the case of the XPVP, the air channels between the particles of the powder pack become rapidly and completely replaced by liquid and a plateau is reached within just 90 s. Overall, the lack of swelling of XPVP favours a potent and rapid wicking action.

       Effect of Storage on Physical Characteristics of Pure Disintegrants Tablets

      Changes of physical characteristics of tablets on storage can affect their disintegration performance.
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      To probe the effect of storage on the physical characteristics of the disintegrants alone, devoid of other formulation factors, we measured changes in hardness, thickness, diameter and LOD of pure disintegrant tablets upon storage (Fig. 3a–d, respectively). Absolute values are reported in Table S1. Three conditions were selected: 1) room conditions inside sealed aluminium composite bags; 2) tablets inside sealed bags incubated in a chamber at 40 °C and 75% RH (to test temperature effect); and 3) open tablets incubated in a chamber at 40 °C and 75% RH (to test combined humidity and temperature effects). Data relative to SSG could not be collected because these compacts were too brittle and crumbled during manual handling.
      Figure thumbnail gr3
      Fig. 3Percentage change in hardness (a), thickness (b), diameter (c) and LOD (d) of pure disintegrant tablets upon storage, compared to the same tablets at time 0. Storage time and storage conditions are indicated in the legend and in the y-axis, respectively. RT = room temperature; sealed 40C 75%RH = inside sealed bags in a chamber at 40 °C 75%RH; open 40C 75% RH = open in a chamber at 40 °C 75% RH. ∗ indicates that values of hardness were below the limit of detection of the crushing strength apparatus. Note that SSG tablets could not be tested because they were too friable to be handled.
      The hardness of both CCS and XPVP tablets decreased upon storage, to an extent that was dependent on the storage conditions: tablets stored for up to 28 days at room temperature or inside the sealed bags in the chamber showed only a slight decrease in hardness, while tablets stored open inside the cabinet became weak (below the limit of detection in the case of XPVP). Therefore, the combined exposure to high temperature and humidity - rather than the high temperature alone – were the most deleterious for tablet hardness. In agreement with the hardness, tablets thickness and diameter changed only moderately at RT and in sealed bags at 40 °C 75% RH, yet they increased massively for tablets left open at 40 °C 75% RH. The values of the tablets’ dimensions after 1 day storage at RT in sealed bags are an indication of elastic recovery.
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      • Desai P.M.
      • Chua S.M.
      • Loh Z.H.
      • Heng P.W.S.
      Effect of moisture sorption on the performance of crospovidone.
      ). Finally, the percentage change in LOD revealed that XPVP tend to absorb more moisture than CCS tablets at all conditions. A clear relation between LOD and hardness cannot be found, as for instance XPVP tablets stored at RT and in sealed bags at 40 °C 75% RH absorbed a greater amount of moisture, yet maintained greater hardness, than CCS.
      The negative effect of humidity on hardness and disintegration properties of XPVP within complex tablet formulations is well documented.
      • Hersen-Delesalle C.
      • Leclerc B.
      • Couarraze G.
      • Busignies V.
      • Tchoreloff P.
      The effects of relative humidity and super-disintegrant concentrations on the mechanical properties of pharmaceutical compacts.
      • Hiew T.N.
      • Johan N.A.B.
      • Desai P.M.
      • Chua S.M.
      • Loh Z.H.
      • Heng P.W.S.
      Effect of moisture sorption on the performance of crospovidone.
      • Sacchetti M.
      • Teerakapibal R.
      • Kim K.
      • Elder E.J.
      Role of water sorption in tablet crushing strength, disintegration, and dissolution.
      Our results on pure disintegrants compact confirm that the physical properties of XPVP tablets were more affected by the storage at 40 °C 75% RH than CCS tablets. Fig. 3b reveals that even in absence of humidity effects (i.e. inside the sealed bag), storage in the cabinet at high temperature triggered a moderate shape-recovery of XPVP (i.e. a ≈5–8% thickness increase). Fig. 4 shows the macroscopic changes occurring to pure disintegrants tablets stored for 1 and 28 days at RT, sealed 40C 75%RH and open 40C 75%RH, upon exposure to 6 drops of water.
      Figure thumbnail gr4
      Fig. 4Effect of storage on morphological changes of pure disintegrant tablets upon exposure to 6 drops of water. Storage conditions are indicated in the first row. RT = room temperature; sealed 40C 75%RH = inside sealed bags in a chamber at 40 °C 75% RH; open 40C 75%RH = open in a chamber at 40 °C 75% RH.
      CCS tablets gel and swell upon exposure to water without macroscopic difference between storage conditions. XPVP tablets stored open for both 1 and 28 days at 40 °C 75% RH show a massive humidity-induced shape-recovery, compared to the same tablets stored at RT and in sealed bags at 40 °C 75% RH, in agreement with Fig. 3b. Interestingly, while tablets stored at RT and in sealed bags at 40 °C 75% RH responded to the water addition with a sudden axial size-expansion, tablets stored open at 40 °C 75% RH, that already underwent shape-recovery in the dry state, did not show any change upon addition to water. This indicates that the premature moisture-induced shape-recovery during the storage open at 40 °C 75% RH, abolished completely the activity of the disintegrant in water. On the contrary, XPVP tablets stored for 1 and 28 days at RT and in sealed bags at 40 °C 75% RH could still absorb water and elicit the axial size-expansion. We can conclude that the disintegrant action of XPVP is at least partially maintained for tablet stored both at RT and at elevated temperature under normal humidity conditions. Thus, humidity, more than temperature alone, seems to negatively affects the action of XPVP.
      In conclusion, the physical properties of XPVP are more influenced by storage than CCS. The combined effect of high temperature and humidity induced a rapid shape-recovery of XPVP compacts on storage, abolishing its disintegration action in water. At RT and elevated temperature, in absence of high humidity, the shape-recovery on storage is only moderate (Fig. 3b), thus XPVP can maintain, at least partially, the ability to expand axially when exposed to fluids.

       Disintegration Time Hydrophobic Tablets at Time 0

      Hydrophobic tablet formulations were developed using HVO, as model compound. This material has been previously used as lubricant, auxiliary binder and even as matrix-forming waxy-based controlled release agent.
      • Rowe R.C.
      • Sheskey P.J.
      • Quinn M.E.
      • Association A.P.
      • Press P.
      HVO's high hydrophobicity (contact angle = 108.4°
      • Jozwiakowski M.J.
      • Jones D.M.
      • Franz R.M.
      Characterization of a hot-melt fluid bed coating process for fine granules.
      ) renders this compound a useful model for the formulation of challenging hydrophobic tablets, over a broad range of compaction force. 10% HVO was incorporated into tablets formulations containing DCP and MCC as filler and dry binder, respectively. Tested formulations differed for the type (SSG, CCS or XPVP) and concentration (1 and 4%) of disintegrant used (Table 1). Each formulation was compressed at four different compression pressures. We compared here the disintegration ability of the three superdisintegrants in challenging hydrophobic formulations.
      Fig. 5 shows the disintegration time of the tablets containing 1% disintegrant, tested immediately after compression. Disintegration times in water, HCl and PB (Fig. 5a–c respectively) were similar for each formulation. Control tablets w/o superdisintegrant broke-up slowly in all media, with disintegration times directly proportional to the compression pressure. The incorporation of each of the three disintegrants could speed-up disintegration compared to the controls, yet to different extent. While SSG and CCS could provide rapid disintegration (disintegration times <100 s), irrespective of compression pressure, XPVP yielded longer disintegration times (up to 264 s), particularly at higher compression pressure.
      Figure thumbnail gr5
      Fig. 5Disintegration time (mean ± SD, n = 6) of hydrophobic tablets containing 1% disintegrant in water (a), HCl (b) and PB (c), prepared at four different compression forces.
      The disintegration times of freshly prepared tablets containing 4% disintegrant are presented in Fig. 6. The influence of both media and compression pressure on disintegration was negligible, in all cases. All tablets containing 4% SSG and CCS show average disintegration times ≤28 s. Tablets containing XPVP, broke up slightly more slowly. Overall, the poorer performance of XPVP was greater at the lower (Fig. 5) than at the higher disintegrant concentration (Fig. 6).
      Figure thumbnail gr6
      Fig. 6Disintegration time (mean ± SD, n = 6) of hydrophobic tablets containing 4% disintegrant in water (a), HCl (b) and PB (c), prepared at four different compression pressures.
      SSG and CCS are known to exert their disintegration action by mainly swelling, while XPVP, which swells minimally (Fig. 1), generates the pressure necessary for breaking up tablets by shape-recovery.
      • Berardi A.
      • Bisharat L.
      • Blaibleh A.
      • Pavoni L.
      • Cespi M.
      A simple and inexpensive image analysis technique to study the effect of disintegrants concentration and diluents type on disintegration.
      ,
      • Desai P.M.
      • Liew C.V.
      • Heng P.W.S.
      Understanding disintegrant action by visualization.
      ,
      • Quodbach J.
      • Kleinebudde P.
      A new apparatus for real-time assessment of the particle size distribution of disintegrating tablets.
      Regardless of the mechanism of disintegration (i.e. swelling or shape-recovery) the wicking ability of the disintegrant in the formulation is the crucial pre-requisite that rapidly provides the water necessary for either the swelling or shape-recovery of the disintegrant to occur all throughout the tablet.
      • Markl D.
      • Zeitler J.A.
      A review of disintegration mechanisms and measurement techniques.
      ,
      • Quodbach J.
      • Kleinebudde P.
      A critical review on tablet disintegration.
      Particularly in the case of hydrophobic formulations wicking relies on the ability of the disintegrant excipient to draw water into the tablet.
      • Caramella C.
      • Colombo P.
      • Conte U.
      • et al.
      Water uptake and disintegrating force measurements: towards a general understanding of disintegration mechanisms.
      The longer disintegration of XPVP compared to SSG and CCS can be explained. First, it should be noticed that the XPVP underperformed particularly at low concentration of disintegrant in the formulation and at high compression pressure (Fig. 5). At 1% concentration, XPVP might have been unable to form a continuous hydrophilic network. The possibility that XPVP particles might have remained separated, even after an initial hydration might be due to: 1) the high distance between the low number of large XPVP particles (median particle size ≈125 μm for XPVP vs ≈ 40 μm for SSG and CCS grades
      JRS Pharma
      Manufacturer website.
      ); 2) the short-range particles swelling (Fig. 1) that did not enable contiguous hydrated particles to contact and transfer the liquid from one another. At the higher compression pressure, as the pores for liquid penetration became even narrower, wicking was further reduced, retarding disintegration even more. On the contrary, SSG and CCS particles, being smaller and more numerous and also swelling more, could enable wicking through a network of swollen particles, and, in turn, activated a rapid burst of the whole tablet, regardless of the compression pressure. In other words, the larger particle size and shorter-range expansion of XPVP might have hindered wicking and in turn disintegration. At 4% disintegrant, with a greater number of XPVP particles in close proximity to each other, a network of disintegrant might have formed upon hydration, driving rapid wicking and disintegration. The grade of XPVP, SSG and CCS used here are the standard grade for direct compression. Although Quodbach and Kleinebudde showed that in hydrophilic tablets the disintegration performances of a coarse and fine grade of XPVP were very similar,
      • Quodbach J.
      • Kleinebudde P.
      Performance of tablet disintegrants: impact of storage conditions and relative tablet density.
      ,
      • Quodbach J.
      • Kleinebudde P.
      Systematic classification of tablet disintegrants by water uptake and force development kinetics.
      this might not hold true for hydrophobic formulations. Future work should further investigate whether the particle size of XPVP can influence the disintegration of hydrophobic tablets.

       Effect of Storage on Disintegration of Hydrophobic Tablets

      Next, we studied the influence of storage on the disintegration times of the same tablet formulations. Immediately after compression, tablets were placed inside small bags. The bags were sealed and stored in a cabinet at 40 °C and 75% RH to simulate storage of the tablets within closed blisters under harsh environmental conditions. Fig. 7 shows the effect of storage time (1, 7, 14, 28 and 56 days) and compression pressure on the disintegration of 1% SSG (A), CCS (B) and XPVP (C) tablets in HCl. Values of standard deviation are reported in Table S2.
      Figure thumbnail gr7
      Fig. 7Effect of storage and compression force on the disintegration time (mean, n = 6) of hydrophobic tablets containing 1% SSG (a), CCS (b) or XPVP (c) in HCl 0.1 M. Colour scale denotes ranges of disintegration time from 0 s (green) to > 900 s (red).
      For the three disintegrants, both compression force and storage time had a negative effect on disintegration, with the slowest disintegration at the highest compression force (20 kN) and at the longest storage time (56 days). However, the extent of these effects varied greatly between disintegrants that ranked in this order: CCS (least affected by compression force and storage) » SSG » XPVP. Tablets, compressed at 20 kN and stored for 56 days, disintegrated in ≈3, ≈12 and ≈ 69 min with 1% CCS, SSG and XPVP, respectively. Figs. S1 and S2 show the effect of storage time and compression pressure on the disintegration of the same tablets in water and PB, respectively. Overall, results are qualitatively similar to those obtained in HCl. Only the disintegration performance of SSG is better in both water and PB, compared to HCl (Fig. 7), due to the greater swelling volume of this disintegrant in water and PB than in HCl (Fig. 1).
      The negative impact of compression pressure on disintegration has been discussed in the previous section. On the other hand, the negative effect of storage on disintegration seen for all formulations (regardless of the disintegrant used) can depend on a morphological change in the tablet. The hydrophobic formulation used here contains HVO, a plastic (at room temperature) and low melting point (61–66 °C) material.
      • Rowe R.C.
      • Sheskey P.J.
      • Quinn M.E.
      • Association A.P.
      • Press P.
      It is possible that at 40 °C storage, a time-dependent bulk diffusion and viscous flow of HVO occurred, altering interparticle bonding and further increasing the plasticity of the matrix.
      The delay of disintegration time as a function of storage time was more pronounced when XPVP was used. Possible causes of the poorer performance of XPVP are: 1) the mechanism of action of XPVP, which might not be ideal to disrupt matrices with a plastic component; and 2) a reduction in the disintegrant functionality upon storage. In regards to the first aspect, the negative effect of storage on disintegration was greater for XPVP than the other disintegrants, probably because the rapid, yet short-range expansion (Figs. 1 and 2) of XPVP could not efficiently disrupt the plastic hydrophobic matrix. Secondly, storage might have directly affected XPVP functionality. We showed in Fig. 3b that pure XPVP tablets stored in sealed bags at 40 °C and 75% RH could regain ≈5–8% of their original thickness. Similarly, Hiew et al. have shown that DCP tablets containing XPVP could increase in thickness after just 1 day of storage, to an extent that was directly proportional to the disintegrant concentration and to the relative humidity.
      • Hiew T.N.
      • Johan N.A.B.
      • Desai P.M.
      • Chua S.M.
      • Loh Z.H.
      • Heng P.W.S.
      Effect of moisture sorption on the performance of crospovidone.
      It is possible that in our hydrophobic formulation, XPVP could undergo a slow plasticisation and softening during storage, regaining size in the direction opposite to compression. Such premature shape-recovery in the dry state dissipated part of the energy stored within the compressed disintegrant particles. Thus, upon exposure to fluids, the disintegration action exercised by XPVP against the tablet scaffold was reduced. Although we cannot totally rule out the possibility that some moisture present in the headspace of the sealed bags might have entered the tablet and pre-activated the disintegrant shape-recovery, we believe that this moisture effect is unlikely or only minimal, as also suggested by Fig. 3.
      In agreement with our findings, Sacchetti et al. had previously shown that for various tablet formulations stored at 40 °C and 75% RH, disintegration was more negatively affected by storage when XPVP was used as disintegrant, rather than SSG and CCS.
      • Sacchetti M.
      • Teerakapibal R.
      • Kim K.
      • Elder E.J.
      Role of water sorption in tablet crushing strength, disintegration, and dissolution.
      SSG and CCS, which do not act predominantly by shape-recovery, and on the contrary show higher swelling capacity than XPVP (Fig. 1) might have maintained a greater disintegrant functionality upon storage.
      • Sacchetti M.
      • Teerakapibal R.
      • Kim K.
      • Elder E.J.
      Role of water sorption in tablet crushing strength, disintegration, and dissolution.
      As CCS performed best, it can be proposed that the good balance of wicking and swelling, rather than a purely swelling behaviour as that of SSG, are necessary for optimal disintegrant functionality in hydrophobic tablet formulations.
      The same set of disintegration tests was conducted for the formulations containing 4% disintegrants (Fig. 8). Values of standard deviation are reported in Table S3. The disintegration of the three formulations was only slightly affected by compression force and storage time. Both increasing compression force and storage time caused a moderate delay in disintegration, particularly in the case of XPVP. Nevertheless, all tablets disintegrated in times ranging between 15 s and 3 min. Similar results were obtained when the same tablets were tested in water and PB (Figs. S3 and S4).
      Figure thumbnail gr8
      Fig. 8Effect of storage and compression force on the disintegration time (mean, n = 6) of hydrophobic tablets containing 4% SSG (a), CCS (b) or XPVP (c) in HCl 0.1 M. Colour scale denotes ranges of disintegration time from 0 s (green) to > 900 s (red).
      The negative effect of storage and compression force on disintegration of XPVP-containing tablets is much smaller when the concentration of the disintegrant in the formulation is increased from 1 to 4%. A greater concentration of disintegrant means that more particles are in near proximity to each other. In this case, wicking through the continuous network of disintegrant particles is rapid and, consequently, the shape-recovery of a large number of disintegrant particles occurs nearly simultaneously. The concurrent action of several disintegrant particles expanding all together might have been sufficient to disrupt the tablet structure rapidly and at once. On the contrary, with the 1% XPVP water ingress was slower and thus only few disintegrant particles expanded simultaneously, liberating small disintegration force at any one time; hence a slow disintegration phenomenon occurred in that case.

      Conclusion

      We showed in this paper that the selection of the appropriate disintegrant is crucial in the case of hydrophobic tablets. The preliminary characterisation of the disintegrants alone revealed that XPVP takes-up water rapidly, yet its expansion is only moderate and short-range compared to the other disintegrants. Also, the physical characteristics of XPVP compacts are more negatively affected by storage than those of CCS. Particularly after storage at high humidity conditions, the macroscopic shape-recovery action of XPVP appeared totally hampered. Upon incorporation of each of the three disintegrants within the hydrophobic formulation the disintegrant performance was generally in this order: CCS (most efficient) > SSG > XPVP. XPVP underperformed particularly upon long storage, at high compression pressure and at the lower disintegrant concentration. The increased disintegration time of XPVP-containing tablets was mainly related to 1) the rapid, yet short-range action of XPVP which might be insufficient to disrupt the plastic matrix; and 2) a partial pre-mature shape-recovery of the disintegrant upon storage. On the contrary, the good balance of swelling and wicking action of CCS, which ensures a rapid liquid penetration into the tablet, seems to guarantee the superior disintegration performance of CCS in hydrophobic tablets.
      Some findings of this study contradict traditional disintegration selection criteria which were derived from (overly) simplified systems. In the interest of increasing the practical relevance, aspects like hydrophobicity and storage effects were included into the design of the present study. Based on our findings, we propose that the relation between disintegration times on storage and disintegration forces
      • Quodbach J.
      • Kleinebudde P.
      Systematic classification of tablet disintegrants by water uptake and force development kinetics.
      developed under the same conditions are to be evaluated in future investigations. Also, further disintegration studies guided by the challenges of “real-life” pharmaceutical formulations, rather than based on the inert hydrophobic model compound used here, are anticipated.

      Acknowledgments

      The authors thank Andrea Geiβ, Christina Schuster and Maja Launer for their technical assistance.

      Appendix A. Supplementary Data

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