ORIGINAL ARTICLE Year : 2010  Volume : 1  Issue : 4  Page : 406414 Detachment and recovery index: A new parameter measuring powder compressibility SAS Aly Department of Research and Development, Chemical Industries Development (CID), Assiut Branch, Assiut, Egypt Correspondence Address: This investigation introduces a simple and reliable approach to measure the compressibility of some direct compression excipients in tablet systems made from compressible components. The claim made here is that: the total reduction, ΔL _{T} , in the thickness of a tablet batch due to compression at a confined machine settings is the integral sum of small reductions generated by the compressible components in the batch. The reduction value, ΔL _{E} , generated by a single or a blend of excipients in a batch could be calculated and was found to correlate to its concentration, C, by the relation: ΔL _{E} =A _{E}.C ^{x}. The constants AE and x concern the reduction tendency, RT, of the excipient particles due to compression, and detachment and recovery index (DRI), respectively. Some physicomechanical parameters characterizing the compression behavior of an excipient in a tablet batch could be determined and were found to be functions of the determine DRI of the excipient in the batch.
Introduction Compressibility of pharmaceutical powders and granules has been a subject of interest to many workers in pharmaceutical technology field since the sixties of the last century. Mani et al.[1] and Panny [2] reviewed and discussed the different models and equations proposed to measure the compressibility of powders and granules. The published models [38] focused the relationship between the compression pressure and the density of the produced compacts. Mani et al. mentioned that the most commonly used models are Heckel, [3] Kawakita and Ludde, [4] and CooperEaton [5] models. Comoglu [9] pointed out that Heckel and Kawakita and Ludde models have not been proven to be successful in relating the densification behavior to the physicomechanical properties of the materials. Moreover, the Heckel model produces curved not linear plots whereas the Kawakita and Ludde model works best for only limited range of materials. Although the equations mentioned in these two models appear very different, it has been mathematically shown that for pressures that are relatively low compared to the yield strength, they are identical in form. Although CooperEaton model provides best fit to compression data, its application is limited to one component system. [9] In a simple approach, Aly [10] showed the compression degree of a powder bed was a function of the free asperities available on the surface of the powder under compression. The thrust of the present study is to introduce a simple and reliable model to measure the compressibility of excipients in tablet systems made of compressible components. Applying this model would minimize the use of instrumented tabletting machines which need calibration and some special handling. Materials and Methods Oxytetracycline hydrochloride (OTH), the model of autocompressible drug material was received from Cid, Assiut Branch, Assiut, Egypt. The direct compression excipients namely, microcrystalline cellulose, MCC, given by Food Manufacture Centre, FMC, Co., Pensylvania, PA, USA; the free flowing spray crystallized maltose and dextrose, celutab, obtained from E. Mendell Co., Pennsylvania, PA, USA; and the direct compression starch, starx, from Stanley Mfg., ILL., USA, respectively, were employed to prepare OTH tablets in this investigation. Magnesium stearate and stearic acid, the lubricants employed, and the analytical grade chemical materials used in this study were purchased from E. Merck, Darmstadt, FRG. Evaluation of Physical Properties of Powders The physical properties of the drug and excipient powder materials such as mean particle size, density, flow rate, repose angles and moisture content (dry weight basis) were determined. The mean particle diameter of a given powder material was determined using sieving technique. For the test, a 100 g sample randomly collected from a given powder material was placed onto the top sieve of a set of standard stainless steel sieves arranged in descending order and mechanically shaken for 5 min using a magnetic shaker. The mean particle diameter of the sample was calculated from the weight fractions retained on the sieves and the mean aperture of two consecutive sieves. The apparent density of a given material was determined by the liquid displacement technique using immiscible liquid and a pycnometer calibrated at room temperature. The mean of three determinations was taken as the apparent density of the given material. The bulk and tap densities and packing fraction of a given powder material was determined as follows: An accurately weighed 100 g sample of the given powder material was carefully poured into a 200 ml measuring cylinder and its volume, υ, was precisely determined. The bulk density, ρB , of the sample was calculated as: ρB = 100/υ. The powder sample was then tapped seven taps (till no change in the volume of the powder sample was observed) and the tap density, ρt, was calculated as the ratio of the weight to the tap volume. The mean of 10 determinations was taken as the bulk and tap density of the given material. Packing fraction, pf of the powder sample was calculated from pf =1[(ρB /ρt )Χ100]. The flow rate and repose angle were determined using the funnel technique and a cathetometer as described by Chukwu. [11] The moisture content (dry weight basis) was determined as mentioned earlier. [10] Formulation and Compression of Tablets Simple mixing technique was adopted to formulate tablets of increasing concentrations of a given single or 1:1 binary blend of excipients using a locally constructed drum mixer of suitable capacity operated at 30 revolutions per minutes for 5 min. The formulations prepared with starx were lubricated with 2% (w/w) stearic acid to produce hard tablets. [12] The other formulations were lubricated with 2% (w/w) magnesium stearate. The lubrication process was carried out for 5 min just prior to compression using the local drum mixer. A single punch tabletting machine (Manesty Machines Ltd., Liverpool, UK) fitted to flat faced punches was adjusted to compress tablets of 0.1 g mean weight and 6.4 mm mean diameter, and of the highest mechanical properties (mainly crushing load and friability) that could be achieved from the batch formulated with the largest concentration of a single or blend of excipients. The machine settings were kept constant throughout compressing the batches prepared from the lower concentrations of the same single or blend of excipients. It was necessary to readjust the machine settings whenever formulations of a new single or blend of excipients was compressed. At each confined machine settings, a control tablet batch was compressed from lubricated OTH powder. Altogether, 300 tablets were compressed from each batch. Applying this compression technique would minimize the fluctuation in compression pressure due to particle size variation. Having been compressed, the tablets were equilibrated over silica gel for 24 h prior to carrying out the evaluation tests to allow for elastic recovery, hardening, and avoid measuring the falsely yield values. Evaluation of Tablets Uniformity of weight and thickness The produced tablets were evaluated for the weight and thickness uniformity. A sample of 20 tablets randomly collected from a given batch was used for the test. The tablets were individually and accurately weighed. The evaluation was carried out in accordance with BP 2000 specification. The thickness of each weighed tablet was determined using a dial micrometer. Calculation of ΔL E of an excipient in a tablet batch. The total reduction, ΔL T , in the thickness of a tablet batch due to compression is generally given by [INLINE:1] where Lo and LF are the thicknesses of the tablet batch before and after compression, respectively. Lo is calculated as [INLINE:2] where w stands for the mean weight of the compressed tablet batch; d, is its mean diameter; x i, stands for the weight fraction of the compressible component (i) in the tablet and (ρB )i is its bulk density, respectively. Accordingly, Eq. (1) can be rewritten as [INLINE:3] It is claimed in this investigation that ΔL T is the sum of small reductions generated by the compressible components in the tablet batch which in this instance are the drug and excipient(s). Equation (3) is thus simply rewritten as [INLINE:4] The reduction in the thickness, ΔL D, effected by the drug in a given batch is calculated from the control tablet batch (compressed from the lubricated drug only) of the set wherefrom the given batch is taken as follows: According to Eq. (2) Lo D , of the control batch of a given set is calculated as [INLINE:5] where w stands for the mean weight of the control batch, d, is its mean diameter; xD , represents the weight fraction of the drug in the tablet and (ρB ) D , is the drug bulk density, respectively. ΔL D is given by [INLINE:6] where Lc is the thickness of the finished control tablet batch. Eq. (6) can be rewritten as [INLINE:7] Dividing Eq. (7) by wxD yields [INLINE:8] where ΔL g , (mm g 1) is the reduction in the height of a column of 1 g lubricated drug powder compressed at the same confined machine settings. ΔL g is practically impossible to obtain. Each set of the compressed batches has its ΔL g value calculated from its control batch. This ΔL g is employed as a reference to calculate ΔL D value affected by the drug in a batch taken from a set. ΔL D for a given batch is calculated as [INLINE:9] where "m" is the weight (g) of the drug material in the batch. According to Eq. (4), ΔL E is given by [INLINE:10] Results Physical Properties of Powder Materials The powders used in this investigation are of wide size variation and, accordingly, of varying surface areas. They possessed adequate flow rates and repose angles ranging from 1.0 to 3.5 g s 1 and from 26 o to 48 o , respectively, which characterize the powder of low flow properties. Blends of excipients did not show improved flow properties. This is shown in the data listed in [Table 1].{Table 1} Physical Properties of Compressed Tablets Uniformity of weight and thickness The data given in [Table 2] show that the batches compressed with starx and MCC/Celutab blend were uniform in weight and complied with the BP 2000. The uniformity of thickness of the studied batches was examined as an additional control of tablet uniformity. The variation in thickness of the studied batches was parallel to those variations in weight.{Table 2} Mechanical Properties of Tablets Porosity, crushing load, and friability The porosity fraction, ε%, of a given tablet batch was calculated from [INLINE:11] where VE stands for the true volume of the excipient(s) in the given batch. VE is given by [INLINE:12] where w i and ρi represent the weight fraction of the component (i) in the tablet and its true density, respectively. [Table 2] shows the porosity of a tablet batch decreased as the excipient concentration, C, in the batch increased. Celutab produced the least porous tablets (porosity ranged from 14.8% to 3.7%). MCC produced less porous tablets. The porosity of the tablets ranged from 9.3% to 5.1% where starx produced porous tablets. Tablets compressed with starx blends with celutab or MCC possessed improved levels of porosity fractions. However, more porous tablets were compressed from MCC/celutab blends. [Table 2] also shows that the crushing loads, H, generally increased as C increased in a tablet batch. Tablets compressed from MCC and celutab possessed almost the same level of crushing load. Starx produced harder tablets. Blends of excipients produced tablets of higher levels of crushing Load. It is clearly seen in [Table 2] that the friability, F, decreased as C increased in a given tablet batch. Tablets produced with starx showed the least friability level followed by those tablets produced with celutab. More friable tablets were produced from MCC. Celutab/starx blend. [Table 2] also shows that the tablets produced with MCC disintegrated after relative long times. Contrary, starx and celutab, in this order, produced fast disintegrating tablets. Batches produced with blends of excipients generally disintegrated after short times Measuring Excipients Compressibility The reduction in tablet thickness contributed by an excipient in a batch denoted as ΔL E and calculated as shown in [Table 3] fits to the relation:{Table 3} [INLINE:13] The constants AE and x calculated using the least squares fits concern the physical reactivity of excipient particles characterized by the reduction in size due to compression and denoted as reduction tendency, RT, and the recovery and detachment index, detachment and recovery index (DRI), of the particles. Discussion This study introduces a simple and reliable mathematical approach to determine DRI as a measure of powder compressibility. In this approach, there is no need to employ calibrated instrumented tabletting machines [3] or/and to deduce constant parameters of the being compressed powders [4],[5] to measure its compressibility. The study also examined the correlations that might exist between DRI and the physical properties of the compressed tablets. The wide size variation and the adequate flow properties of the powder materials employed in this investigation caused the segregation observed upon compression and therefore nonuniform tablet batches were produced. Formulations exhibiting continuous, uniform and controlled flow could be produced mixing excipients possessing glidant effect such as starx [12] or MCC. [13] Contributing such excipients to formulations could minimize or diminish the interparticulate friction to a level favorable to uniform and continues flow and therefore uniform tablets could be produced. Sugary excipients such as celutab possess high brittleness indices. [14] This excipient deforms under compression and generate fine particles which find its way to percolate and fill the spaces between large particles to decrease the voids. As compression process progresses the percolation process continues and results in producing compacts of low voids fraction. [4] This percolation process proceeds in a smaller degree with starx due to its smaller brittleness index. [14] Due to its small brittleness index, [14] MCC failed to generate new surfaces upon compression, [15] therefore the tables made with this excipient had small porosity fractions. Celutab/starx blends produced the least porous tablets followed by MCC/starx. On the other hand, celutab/MCC mix produced porous tablets, i.e., the compression behavior of MCC was not improved by mixing with celutab. Excipients of high bonding particles such as celutab and starx consolidate, deform and bond into compacts of high levels of crushing strength under small pressure. This is supported by the liquid film surface theory of bonding. [15] In addition, the high moisture content of these excipients play a vital role to promote particles bonding. It seems that the brittleness indices of these excipients had a little effect on particles bonding of and, therefore, compacts of enhanced mechanical properties were produced from these excipients. MCC particles were reported to show a little deformation and fusion under pressure. [15] Therefore, it was not surprising to compress porous compacts of low crushing loads from this excipient. Blends of celutab with other excipients produced tablets of enhanced crushing load levels properties. [Figure 1] shows the exponential decay of ε% of the studied batches fits the relation:{Figure 1} [INLINE:14] where εo represents the porosity fraction of the tablets made with no excipient (control batch) and kε0, is a dimensionless parameter concerning the percolation of fine particles to fill the spaces between large particles during compression. It is the percolation index, PI, of a named excipient in a given tablet system. kε values obtained for the tested excipients and their blends are given in [Table 4]. Excipients of highly bonding particles generated low kε values. It is seen in [Figure 2] that the crushing loads, H, exponentially increased as C increased in a given tablet system and the relationship: [INLINE:15] holds. Ho and k H stand for the crushing load of the control tablet batch and the hardness concentration profile, HCP, of an excipient in a batch. [Table 3] shows that excipients of high bonding particles possessed high HCP values. Mixing of such excipients with excipients of poorly bonding particles yielded formulations of improved compressibility. It should be clear in mind the negative effect of brittleness on the crushing load of the produced compacts.{Figure 2} [Figure 3] shows that friability, F, correlates to C in a give batch by the relation:{Figure 3} [INLINE:16] where Fo stands for the friability of the control tablet batch and k F is the resistance to abrasion index, RAI, of the tablets. [Table 3] shows that the excipient of particles of high bonding potentiality generated higher RAIs. [Figure 4] shows that the disintegration time, Dt , of the a tested tablet batch is generally excipienttype and concentration dependent factor. Starx (starchy) and celutab (soluble) excipients produced fast disintegrating tablet. The incorporation of such excipients in formulation shortened the disintegration time. [Figure 4] also shows that the disintegration rate constant, D, g min 1 , is correlated to C in a given batch by the relation:{Figure 4} [INLINE:17] The constants, Ad and kd given in [Table 4] concern the D of the control batch and a parameter indicative of the disintegration capacity, D C, of the excipient in the batch, respectively. Starx possessed the highest DC value [Table 4]. DC of MCC could be improved by contributing an excipient of high DC in formulation.{Table 4} [Figure 5] represents the relationship existing between ΔLE and C for the studied tablet batches. [Table 4] clearly shows that cellulose and starch excipients possessed higher RT values. Their particles could absorb the compression pressure and deform where the particles of the brittle excipients such as celutab did not show such physical reactivity toward the compression pressure. The RT of such brittle materials would be improved by mixing with excipients of higher RT values. However, celutab and starx, in this order, generated the least DRI value, i.e., they are more compressible. This is supported by the liquid surface film theory of bonding. [14] Higher DRI value is recorded for MCC molecules, i.e., it is comparatively less compressible as explained above [Figure 6].{Figure 5}{Figure 6} Conclusions Tablet weight and dimensions could be employed to measure the compressibility of the excipients in direct compression tablets. This simple and reliable approach is not limited to evaluate powder compressibility in direct compression tablet systems. It can be successfully employed to measure the binding properties of binders in wet granulation tablets. The introduced approach however failed to account for the energy consumed in compressing powders into tablets. Acknowledgments My deepest gratitude goes to Professor Dr. O.K. Udeala, the Dean, Faculty of Pharmacy, Port Harcourt University, Port Harcourt, Nigeria and to Professor Dr. A.M. Sakr, The distinguished Professor, AlKaayal Chair, Faculty of Pharmacy, King Saud University, Al Riaydh, KSA, for what they have taught which is beyond school learning. References


