Linking API material property in high load formulations to the roller compaction process
Keywords: Roller compaction, dry granulation, high load formulation, brittle fracture index, ribbon, tablet, compressibility, compactibility.
There is considerable interest in formulations with high active pharmaceutical ingredient (API) load, for reasons including lower patient tablet burden and therefore, potentially improved patient adherence. This remains a challenge not least because most APIs are poor flowing.
Roller compaction (RC) is a granulation technique utilised in the pharmaceutical industry to improve the flow of powders. It is especially useful for APIs which are heat and/or moisture sensitive. However, due to a phenomenon termed loss of reworkablilty, RC often results in a reduction of tablet tensile strength (TS). Therefore, a balance between TS and flow improvement is often sought. To achieve such balance, an understanding of material property and RC process parameters is needed. Material properties such as Brittle Fracture Index (BFI) govern a powder’s behaviour during compaction and compression processes.
In this study; two APIs, ibuprofen (BFI = 0.12) and compound A (BFI = 0.44), with distinct material properties were formulated at high load in an attempt to link material properties with RC process. Keeping all other RC parameters constant and varying roll force only, both plastic-behaving ibuprofen and brittle compound A demonstrated a reduction in tablet tensile strength with increasing roll force. However, ibuprofen showed greater loss in reworkability. For both APIs, a roll force of 6 kN/cm was sufficient to attain granules of appropriate size and low fines. Ibuprofen did not show a conclusive correlation between roll force and flow, however, improved flow was seen in compound A with increasing roll force.
In the process of manufacturing tablets, a number of problems can arise including segregation, poor content uniformity and poor flowability of primary powder. One method for dealing with such issues is granulation. Typically, wet granulation is employed; however, this can be unsuitable for active pharmaceutical ingredients (APIs) which are moisture or heat sensitive (Aulton and Taylor, 2013). Dry granulation by roller compaction is another technique that can be utilised to achieve uniform and better flowing agglomerates (Bindhumadhavan et al., 2005) of specified size distribution. Roller compaction (RC) is the consolidation of powders by application of pressure on two counter-rotating rolls to form densified compacts (ribbons) which are then milled to produce granules. RC, which in essence is a continuous process, solves problems associated with an APIs sensitivity to heat or moisture but often leads to another issue – reduced tablet tensile strength (Sun and Kleinebudde, 2016 Malkowska and Khan, 1983). This phenomenon has been widely reported in the literature, (Mosig and Kleinebudde, 2015, Eriksson and Alderborn, 1995, Wu and Sun, 2007, Herting and Kleinebudde, 2008). Typically, these studies exclude the presence of an API and none of these studies look specifically at high load API formulations. High percentage (30 %) API load allows i) the tablets produced at development stage to be closer to commercialisation target; ii) a reduction in patient tablet burden, potentially leading to increased patient adherence; and, iii) the behaviour of the formulation in response to compaction and compression to be highly attributable to the API material properties.
One fundamental material property is Brittle Fracture Index (BFI), which indicates a material’s preferred method for the relief of tension arising from compaction and compression (Hiestand et al., 1977). BFI is the ratio of tensile strength of a compact with a hole (flawed) to an intact compact. The hole acts as a tension concentrator. Theoretically, a very brittle flawed compact will show a tensile strength of about one-third that of an intact compact (Hiestand et al., 1977). Materials with low BFI (< 0.3) undergo plastic deformation preferentially while materials with BFI > 0.3 fragment (Hiestand et al., 1977 Jain, 1999). Wu and Sun (2007), proposed that the tablettability of brittle excipients is insensitive to granule size enlargement while Malkowska and Khan (1983), found the reworking potential of plastic excipient to be higher. In this study, a plastic API, Ibuprofen (BFI = 0.12) and a brittle API (BFI = 0.44) were formulated in an attempt to link material property to dry granulation by roller compaction. As the pharmaceutical industry aligns more towards the use of predictive tools and modelling, it is vital that studies with an in-depth look at the influence of API properties on solid dosage manufacturing process feed into these predictive tools.
RC process parameters including roll gap, roll speed, screw speed and roll force undoubtedly influence the properties of ribbons and granules produced, which in turn affects the quality of tablets produced. Characterising the products of RC enables a better understanding of the process, making it possible to define the suitability of RC as well optimal parameters. Inghelbrecht and Paul Remon (1998) varied multiple parameters and found that pressure had the most influence on the quality of granules. In this study, roll gap and roll speed were kept constant while the influence of varied roll force on the compaction behaviour of two APIs with distinct BFI was investigated.
2 Method and Materials
The materials used in this study were microcrystalline cellulose (Avicel PH101, FMC BioPolymer, USA), lactose monohydrate (Fast Flo 316, Foremost, USA), sodium starch glycolate (Explotab, JRS Pharma, Germany), magnesium stearate (Mallinckrodt, USA), ibuprofen (Ibuprofen 38, BASF, Germany) and compound A (Pfizer Ltd, UK).
Details of the formulation are given in Table 1.
Formulation for ibuprofen and compound A blends *
|Batch||Material||Function||Percentage quantity (% w/w)|
|Sodium starch glycolate||Disintegrant||5|
|Sodium starch glycolate||Disintegrant||5|
*Total mass of each formulation = 8 KG.
2.3 Roller compaction
Roller compaction was carried out on a Gerteis Mini Pactor® (Gerteis Maschinen + Process engineering AG, Switzerland) with knurled roll surfaces, equipped with an integrated mill and a 1000 µm rasping screen. For both batches, the mill was operated at 50 RPM, with an oscillating mill angle of 250º clockwise and 270º counter clockwise. The equipment was run at a fixed roll speed (2 rpm) with gap control ON and set at a roll gap of 2 mm. Roll force was varied according to Table 2.
Roll forces utilised for roller compaction of compound A and ibuprofen
|Roll force (kN/cm)|
Roller compaction was carried at ambient temperature and humidity.
2.4 Ribbon solid fraction
The solid fraction (SF) of ribbons was determined using two methods, the first based on the material throughput, according to Nkansah et al. (2008) (Equation 1) and the second on physical measurement of the ribbons (Equation 2).
k = void correction factor, k = number of knurled ribbon sides; (n = 5).
2.5 Ribbon Porosity
Ribbon envelope density was measured with a GeoPyc 1365 Pycnometer (Micromeritics, USA). The chamber diameter, conversion factor and consolidation force used were 19.1 mm, 0.2964 cm/mm and 38.0 N respectively for compound A and 0.5240 cm/mm and 25.4 mm, 51.0 N for ibuprofen. Dry Flo® was used as the medium for measurement. Ribbon porosity was then determined according to Equation 3.
2.6 Ribbon tensile strength
Ribbon tensile strength (σ) was determined by three-point beam bending test using a TA HD Plus Texture Analyser equipped with a 1 kg load cell (Stable Micro Systems, UK), according to Equation 4.
True density measurements of API and blends were performed with an Accupyc II Helium Pycnometer (Micromeritrics, USA). The sample cup of known mass and volume was filled with each material and all measurements were performed after calibration, (n = 2).
2.8 Bulk and tapped density measurement
Bulk and tapped density were measured according to USP <616>, Carr’s index was calculated from Vtand V0 according to Equation 5 (n = 2).
true = true density, A = cross sectional area of tablet, D = tablet diameter, Tc = Cup thickness, Vc = Volume of cup. Filling was performed manually with a tabletting run time of 0.945 s. Compression was carried out across a range of forces (15 – 0.5 kN) under controlled temperature and humidity, 20 ºC and 45 % RH (n = 2). The crushing force of each tablet was measured with a C50 Hardness Tester (Holland, UK) and along with the dimensions of the tablet measured with a calliper (Mutitoyo, Japan), tablet tensile strength was determined according to Equation 7 (Pitt et al. (1988)):
2), Vc = Volume of tablet cup (cm3), Tc = cup thickness (mm), t = overall thickness (mm).
2.13 Statistical analysis
All statistical analyses were performed on Graphpad Prism 7.0 software (GraphPad Software Inc, USA). A significant different refers to a p value of <0.05 (Mann-Whitney U Test).
3 Results and discussion
3.1 Ribbon character
Material properties govern the compactibility of powders (Eriksson and Alderborn, 1995) in the formation of ribbons, and the characteristics of the ribbons produced may play a role downstream in the compressibility of granules during tabletting. The process parameters used for roller compaction undoubtedly had a role to play in the characteristics of ribbon produced. Increasing roll force resulted in an increase in powder flow into the feed auger which required higher torque for compaction into ribbons (Figure 1).
The torque required to meet each desired roll force was marginally higher for ibuprofen compared to compound A, although this difference was not significant. The difference may be due to compound A flowing less freely through hopper, resulting in low amount of the material being available at each point in time and therefore requiring slightly less torque to achieve compaction at that roll force. However, in general for both materials, a linear trend of increasing roll torque was seen with increased roll force.
Solid fraction describes the density of a compact and is sometimes described in terms of porosity of a compact. Typically, a solid fraction of around 0.6 – 0.8 is sought for ribbons while a solid fraction of 0.80 – 0.9 is desirable for commercial tablet manufacture. In this study, ribbon solid fraction was measured by throughput and calliper methods while ribbon porosity was measured by pycnometry (Figure 2).
Figure 2 (A,B,C)
There was consensus between both methods in the measured solid fraction, with ibuprofen producing denser ribbon at each specific roll force. Being a plastic material, its ability to undergo deformation on application of force is greater than that of compound A. Ribbon porosity followed a similar trend to that seen in calculated solid fraction. Compound A produced more porous ribbons compared to ibuprofen. However, in both batches, the porosity of the ribbons produced correlated inversely with increasing roll force.
A relationship was present between solid fraction and tensile strength of ribbons, with the plastic material (ibuprofen) requiring compaction to a higher solid fraction to achieve a given tensile strength. This behaviour is consistent with the literature (Jain, 1999) and can be attributed to the dominant densification method for the APIs used in this study. To achieve a compact, brittle compound A primarily fragments creating new surfaces with which it forms new adjacent inter-particulate bonds. Ibuprofen, although it may follow a similar path, does this to a lower extent; resisting fragmentation in preference to deformation (Jain, 1999). The result of these responses to compaction was that compound A ribbons showed a higher tensile strength at each given solid fraction.
3.2 Granule character
When the frictional forces that keep powders cohesive are overcome, they flow (Aulton and Taylor, 2013). Poor flowing powders can have implications such as poor tablet content uniformity. While the true density of a powder remains the same, bulk and tap density of the different granule lots gives information of the packing arrangement of particles, which can vary in response to shear. Figure 4 shows the tap and bulk densities as well as the Carr’s Index category of the APIs, blends and granules in this study.
Essentially, bulk and tapped density gives an indication of the propensity of a powder to consolidate, which in turn gives an indication of flow (Aulton and Taylor, 2013). Carr’s Index calculated from bulk and tapped density classified compound A and its blends as “very poor”. The granulation process improved flow slightly. However, there was no substantial improvement in the flow of compound A when the roll force was increased from 2 kN/cm up to 10 kN/cm. The pure ibuprofen API had similarly poor flow properties to compound A; however, granulation with a roll force of 4 kN/cm or above lead to improved flow (Figure 4).
Additional flow measurements were carried out with by ring shear testing (RST), which determines powder flow after a fixed pre-consolidated load. Figure 5 presents the effect of roller compaction on flow function co-efficient (FFC). Compound A demonstrated an increase in FFC in response to increasing roll force. However, according to RST, roll force increase appeared to have no substantial effect on the flow of the ibuprofen granules produced.
Roller compaction produces granules with a larger particle size than the ingoing powders. This is advantageous in the improvement of flow properties (Bindhumadhavan et al., 2005), and therefore the expectation in this study was an improvement in the FFC with increasing roll force. The improvement in FFC seen in compound A, did not match Carr’s compressibility Index values, although the significance of improvement in FFC has been previously disputed (Freeman et al., 2016). Powder flow is understood to be affected by humidity changes (Aulton and Taylor, 2013, Emery et al., 2009). As RST was carried out under controlled humidity (50 %), it is possible that compound A responds to a larger extent to humidity changes, hence the improvement in flow seen. Moreover, this study was designed specifically to incorporate high API load (30 %) and given that both APIs constitute ca. one-third of the entire formulation, it possible that the free-flowing characteristics of excipients are masked by high quantity of poor-flowing API.
The SEM image of compound A indicated a thin, ‘fluffy’, needle-shaped material as opposed to ibuprofen which had a crystalline structure that appeared to have more rigour (
Figure 6). In both batches, it was difficult to quantify from SEM images, the effect of roller compaction on the granules. However, it could be concluded that at a press force of 10 kN/cm the presence of smaller particles surrounding granules (which probably comprise fines), was less obvious and the granules appeared more compact.
Particle shape has been found to have an influence on flow character (Podczeck and Mia, 1996). In line with studies by Podczeck and Mia (1996), needle-shaped compound A-containing granules had poorer flow compared to ibuprofen granules. An in-depth look at particle shape using Sympatec QICPIC technology determined the aspect ratio of the granule lots. Aspect ratio is a measure of sphericity of particles and both APIs showed a shift in aspect ratio from zero towards 1 with increasing roll force (Figure 7). The distribution of this shift in aspect ratio also correlated with roll force such that granules formed at 10 kN/cm had the highest distribution of higher aspect ratio.
Essentially, Figure 7 suggests that increasing the roll force at which dry granulation was carried out increased the sphericity of the granules produced. Sphericity was postulated to correlate with flow and compound A showed this improvement in flow when measured with RST, while ibuprofen did not show any meaningful difference.
It is important to consider the variety of factors that could affect flowability, including the presence of large quantities of fines which have the propensity be cohesive and poor-flowing relative to granulates (Aulton and Taylor, 2013). Both batches exhibited a bimodal particle size distribution. The peaks on the left are representative of the fines while the peaks on the right can be attributed to the granules (Figure 8). The particle size of the granules, ca 1000 µm, coincide with the mesh of the rasping screen used for milling, which provided a ‘cut off’ particle size.
For both batches, the blends had a visibly smaller particle size, seen as a peak around 100 µm (Figure 8). However, roller compaction reduced the fines and caused a shift in the particle size towards 1000 µm. Increasing the roll force up to 6 kN/cm resulted in a reduction in fines present within the granulates, above this roll force there was no obvious reduction in the number of fines within the formulations.
Table 3 gives a summary of the mean (± SD) D[v,0.1], D[v,0.5] and D[v,0.9] of the blends and granules, which are representative of the size under which 10 %, 50 % and 90 % respectively of the bulk particles lie.
Mean (± SD) D[v,0.1], D[v,0.5] and D[v,0.9] of compound A and ibuprofen blends and granules.
|D[v,0.1] (µm)||D[v,0.5] (µm)||D[v,0.9] (µm)|
|compound A blend||5.13 (± 0.03)||97.43 (± 0.28)||223.02 (± 0.42)|
|compound A 2 kN||49.35 (± 0.49)||172.82 (± 0.49)||964.13 (± 18.29)|
|compound A 4 kN||52.08 (± 0.72)||288.87 (± 7.01)||1144.51 (± 17.2)|
|compound A 6 kN||54.78 (± 0.98)||492.17 (± 8.50)||1201.9 (± 10.81)|
|compound A 8 kN||47.93 (± 0.12)||394.08 (± 2.1)||1136.53 (± 20.52)|
|compound A 10 kN||48.67 (± 1.13)||392.54 (± 1.93)||1059.05 (± 20.61)|
|Ibuprofen blend||19.14 (± 0.09)||66.00 (± 0.20)||170.00 (± 0.23)|
|Ibuprofen 3 kN||42.36 (± 0.74)||174.89 (± 6.89)||861.13 (± 38.84)|
|Ibuprofen 4 kN||46.90 (±0.87)||267.37 (± 15.58)||1009.68 (± 24.65)|
|Ibuprofen 6 kN||49.93 (± 1.29)||387.69 (± 3.69)||997.34 (± 20.53)|
|Ibuprofen 8 kN||41.43 (± 1.01)||316.62 (± 4.23)||981.05 (± 8.52)|
|Ibuprofen 10 kN||41.28 (± 0.84)||305.48 (± 7.25)||994.48 (± 16.68)|
Comparison of the D[v,0.1] values of compound A and Ibuprofen shows that in both cases roll compaction increased the particle size and decreased the level of fines within the granulates. To further confirm a reduction in fines as a result of roll compaction, the percentage of particles within the granulates with sizes of 15 – 200 µm is shown in Figure 9.
Similarly to the D [v,0.1] values, there was a decrease in the level of fines present with increasing roll force up to 6 kN/cm, after which there was no further reduction in fines. Looking at the coarse particles in the compound A size distribution (Figure 8, Table 3.), increasing the roll force from 2 kN/cm up to 6 kN/cmincreased the D[v,0.9]. Following this, there was no further increase in D[v,0.9] in response to increasing roll force. In the case of ibuprofen, from 4 kN/cm, increased roll force had no tangible increase in the D[v,0.9] values obtained. Interestingly, a roll force of 6 kN/cmin both batches appeared to produce the highest distribution of coarse particles. Above a roll force of 6 kN/cm,there was no further increase in granule particle size distribution.
Overall, for both formulations, a roll force of at least 6 kN/cm was required to attain granulates of appropriate size and low fines. In this study, milling was carried out as an integrated process with roller compaction. The benefit of this included efficiency. It would be interesting to study the influence of ‘by-pass’ blends on D[v,0.1] values or fines. One approach to doing so is to collect the ribbons produced by compaction and mill them as a separate entity.
3.3 Tabletting behaviour
Compactibility describes a powder’s propensity to form compacts with sufficient resistance to further deformation following compression. Figure 10 depicts the compactibility of blends and granules of compound A and ibuprofen, represented as a plot of tensile strength against solid fraction.
In all batches, there was an exponential increase in tensile strength with rising solid fraction. However, the bulk blend produced tablets of higher tensile strength compared to the granules (Figure 10). This was due to a well-studied phenomenon termed “loss of reworkability” or “work hardening” (Sun and Kleinebudde, 2016) attributed to shear imparted by the roller compaction process (Mosig and Kleinebudde, 2015).
The loss of reworkability was seen more obviously in the tensile strength of tablets produced from granules generated at the highest roll forces (10 kN/cm). This is because of increasing resistance by the granules to deformation under the compression process of tabletting due to inherent work hardening imparted by preceding roller compaction process. Additionally, increased granule size, seen as a result of increasing roll force in our study, is also thought to have an influence on tensile strength loss. Sun and Himmelspach (2006), found that enlargement of granules resulted in loss of tablettability. Intuitively, larger granules are expected to possess less intimate contact leading to poorer tensile strength.
A robust tablet should have the properties of a plastic material (good compressibility) and also a brittle material, in the form of high tensile strength. Here, the amount of MCC, which is a plastic excipient (Perez-Gandarillas et al., 2016), was slightly higher in compound A formulation. This is common practice to ensure brittle materials such as compound A can attain the compressibility required for a viable tablet. Wu and Sun (2007) reported that the tablettability of brittle components is largely insensitive to increasing granule size and proposed this as a scientific basis for the practice of inclusion of brittle components such as lactose in formulations. In that study, a very low roll force was used (0.6 kN/cm) and not varied. Thus, the Wu and Sun (2007) study considered one aspect of the impact of roller compaction – size increase – but not necessarily the degree of work hardening. The data produced in our study did not fully support findings by Wu and Sun (2007), but did show that increasing roll force had a lower impact on the reworkability of brittle compound A than it did for plastic ibuprofen. In practice, both work hardening and increasing size due to granulation are likely to play a synergistic role in the reduction of tablet tensile strength observed (Sun and Kleinebudde, 2016), with the former being slightly dominant .
Comparing the tensile strength of tablets formed by compound A granules and blend to those formed by Ibuprofen, compound A produced tablets of higher tensile strength at a given solid fraction (Figure 10). This could be explained by the fragmentation behaviour of compound A in response to compression stress, leading to the formation of new surfaces with which it forms inter-particulate bonds and solid bridges (Eriksson and Alderborn, 1995). Whereas ibuprofen, being a plastic material, mainly deforms, with less propensity to form new surface area and hence the lower tensile strength observed. Eriksson and Alderborn (1995) propose that the number of bonds formed is attributed to fragmentation while deformation governs the force. Fragmentation such as that seen with compound A appeared to form a larger number of inter-particulate bridges that translated into increased tensile strength of tablets.
As mentioned earlier, the target tablet solid fraction for commercial manufacture is around 0.80 – 0.9. Figure 11 displays tensile strength, at a solid fraction of 0.85, of tablets produced from granules of Ibuprofen and compound A at a range of roll forces. Consistently, at this solid fraction compound A produced tablets of significantly higher tensile strength. Tablets from compound A and Ibuprofen blends at this solid fraction had a tensile strength of 1.30 MPa and 0.80 MPa respectively.
As both tablets from brittle and plastic APIs showed reduced tensile strength following roller compaction, the relative loss in reworkability at the ideal solid fraction (0.85) was determined by the loss in tensile strength between the blend and the highest roll force used in this study (10 kN/cm). Compound A had a relative loss in reworkability of 45 % compared to 71 % seen with Ibuprofen. As discussed, this showed that both sets of materials experienced a loss in reworkability but compound A did so to a lower extent.
Compressibility describes a powder’s ability to become reduced in volume in response to applied pressure. Compound A required a higher compression stress than ibuprofen to achieve a given solid fraction. This may be related to the inherent properties of each material and therefore their preferred response to applied pressure (Mosig and Kleinebudde, 2015). Ibuprofen, being a plastic material can readily undergo deformation with less force input, hence it reached a higher solid fraction at lower compression stress (Liu et al., 2013). On the other hand, compound A required the input force to be higher to attain the same solid fraction (Figure 12).
At approximately, 200 MPa compound A formulations start to plateau in compressibility irrespective of increasing applied pressure. This same effect was seen but at a much lower compression stress (~ 125 MPa) in the ibuprofen batch. The behaviour observed is consistent with findings by Patel et al. (2008), who reported similarly low compression stress in ibuprofen. Specifically, at a tablet solid fraction of 0.85 the compression stress seen in all compound A tablets was significantly higher than those of Ibuprofen. Figure 12 shows that, for both materials, there was no tangible difference in the compressibility between blends and granules compacted at various roll forces. This observation was consistent for both compound A and ibuprofen. In essence, these findings demonstrate that the compressibility of plastic and brittle materials are unaffected by roller compaction.
The aim of this study was to create a link between the inherent material properties of APIs and their behaviour in response to roller compaction process. Formulations containing brittle compound A (BFI = 0.44) produced ribbons of higher tensile strength at a given solid fraction, in comparison to plastic ibuprofen (BFI = 0.12). On tabletting of the granules produced from the milled ribbons, brittle compound A maintained higher tensile strength relative to ibuprofen. Ibuprofen compressed relatively easily, achieving the target solid fraction under much lower compression stress. However, the roller compaction process did not have any effect on the compressibility of either brittle compound A or plastic ibuprofen. Both sets of APIs showed loss of reworkability in response to increasing roll force applied during roller compaction. The brittle compound A, however, was less susceptible to reworkability loss due to its ability to form inter-particulate bridges with new surfaces formed during fragmentation. As a result of this loss of reworking, a decrease in tensile strength of tablets, at a target solid fraction of 0.85, correlated with increased roll force. Roller compaction also increased the particle size of both batches; a roll force of 6 kN/cm was required to attain granules of appropriate size and low fines. With regards to flow, the response of Ibuprofen to increasing roll force was inconclusive however, compound A appeared to improve in flow with increasing roll force. The results demonstrate that RC is potentially applicable in the production of tablets containing high load brittle or plastic API.
Aulton, M.E., Taylor, K., 2013. Aulton’s Pharmaceutics: The Design and Manufacture of Medicines. Churchill Livingstone/Elsevier.
Bindhumadhavan, G., Seville, J.P.K., Adams, M.J., Greenwood, R.W., Fitzpatrick, S., 2005. Roll compaction of a pharmaceutical excipient: Experimental validation of rolling theory for granular solids. Chemical Engineering Science 60, 3891-3897.
Emery, E., Oliver, J., Pugsley, T., Sharma, J., Zhou, J., 2009. Flowability of moist pharmaceutical powders. Powder Technology 189, 409-415.
Eriksson, M., Alderborn, G., 1995. The effect of particle fragmentation and deformation on the interparticulate bond formation process during powder compaction. Pharm Res 12, 1031-1039.
Freeman, T., Vom Bey, H., Hanish, M., Brockbank, K., Armstrong, B., 2016. The influence of roller compaction processing variables on the rheological properties of granules. Asian Journal of Pharmaceutical Sciences 11, 516-527.
Herting, M.G., Kleinebudde, P., 2008. Studies on the reduction of tensile strength of tablets after roll compaction/dry granulation. Eur J Pharm Biopharm 70, 372-379.
Hiestand, E.N., Wells, J.E., Peot, C.B., Ochs, J.F., 1977. Physical Processes of Tableting. Journal of Pharmaceutical Sciences 66, 510-519.
Inghelbrecht, S., Paul Remon, J., 1998. The roller compaction of different types of lactose. International Journal of Pharmaceutics 166, 135-144.
Jain, S., 1999. Mechanical properties of powders for compaction and tableting: an overview. Pharmaceutical Science & Technology Today 2, 20-31.
Liu, L.X., Marziano, I., Bentham, A.C., Litster, J.D., White, E.T., Howes, T., 2013. Influence of particle size on the direct compression of ibuprofen and its binary mixtures. Powder Technology 240, 66-73.
Malkowska, S., Khan, K.A., 1983. Effect of Re-Conpression on the Properties of Tablets Prepared by Dry Granulation. Drug Development and Industrial Pharmacy 9, 331-347.
Mosig, J., Kleinebudde, P., 2015. Critical evaluation of root causes of the reduced compactability after roll compaction/dry granulation. J Pharm Sci 104, 1108-1118.
Nkansah, P., Wu, S.-J., Sobotka, S., Yamamoto, K., Shao, Z.J., 2008. A Novel Method for Estimating Solid Fraction of Roller-Compacted Ribbons. Drug Development and Industrial Pharmacy 34, 142-148.
Patel, S., Kaushal, A.M., Bansal, A.K., 2008. Compaction behavior of roller compacted ibuprofen. Eur J Pharm Biopharm 69, 743-749.
Perez-Gandarillas, L., Perez-Gago, A., Mazor, A., Kleinebudde, P., Lecoq, O., Michrafy, A., 2016. Effect of roll-compaction and milling conditions on granules and tablet properties. Eur J Pharm Biopharm 106, 38-49.
Pitt, K.G., Newton, J.M., Stanley, P., 1988. Tensile fracture of doubly-convex cylindrical discs under diametral loading. Journal of Materials Science 23, 2723-2728.
Podczeck, F., Mia, Y., 1996. The influence of particle size and shape on the angle of internal friction and the flow factor of unlubricated and lubricated powders. International Journal of Pharmaceutics 144, 187-194.
Sun, C., Himmelspach, M.W., 2006. Reduced tabletability of roller compacted granules as a result of granule size enlargement. Journal of Pharmaceutical Sciences 95, 200-206.
Sun, C.C., Kleinebudde, P., 2016. Mini review: Mechanisms to the loss of tabletability by dry granulation. Eur J Pharm Biopharm 106, 9-14.
Wu, S.-J., Sun, C., 2007. Insensitivity of Compaction Properties of Brittle Granules to Size Enlargement by Roller Compaction. Journal of Pharmaceutical Sciences 96, 1445-1450.
Cite This Work
To export a reference to this article please select a referencing stye below:
Related ServicesView all
Related ContentAll Tags
Content relating to: "Pharmacology"
Pharmacology involves the study of drugs and how they affect the body. A pharmacologist contributes to drug development by researching and testing how the body reacts to medication, and whether the medication can have a positive impact on the body in terms of fighting illness and disease.
Cost Effectiveness Analysis of HCV Medication
Introduction Egypt has the highest prevalence of hepatitis C virus (HCV) in the world (1) . HCV was estimated to affect 10% of 15-59 year olds in 2015, therefore making it one the country’s leading...
Leptospira: Pathogenesis, Genomics, Antigen, Immune Response and Vaccines
Table of Contents I. Acknowledgments II. Table of Contents III. Abstract 1. Introduction 2. Leptospira at Genomics Level 3. Pathogenesis 3.1. Pathogen Entry and invasion 3.2. Virulence...
Hepatic Complications of Oral Contraceptive Pills and Estrogen: Controversies and Update- Adenoma and Beyond
Hepatic complications of oral contraceptive pills and estrogen: Controversies and update- adenoma and beyond. Abstract Hepatic complications of the oral contraceptive pills and estrogen may inclu...
DMCA / Removal Request
If you are the original writer of this dissertation and no longer wish to have your work published on the UKDiss.com website then please: