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Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian1, C. Tian2, X. Ke2* Pharmacy Experimental Center, 2Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China *Correspondence: [email protected]
1
LubriTose SD is a new co-processed excipient consisting of spray-dried monohydrate lactose and distilled glyceryl monostearate. In this study, the new self-lubricating excipient LubriTose SD was characterized from the aspects of powder technological properties and tableting properties. Micromeritic properties, including particle shape, size distribution, flowability, compressibility, and also the dilution potential were determined. Its applications in powder direct compression have been evaluated, including the effects on flowability, compressibility, the lubricating ability, hygroscopic drugs stability, content uniformity of the low-dose drugs and dissolution of poorly soluble drugs. LubriTose SD is 100 μm with very uniform size distribution and with spherical shape, shows the best flowability, has the same deformation mechanism with the spray-dried monohydrate lactose, has high dilution potential to the hydrophobic drug and has improved function of drug tableting. Its lubricating effect is satisfactory. The results of the investigation imply that the LubriTose SD is a good co-processed excipient with self-lubricating properties, which is promisingly suitable for powder direct compression. Key words: Co-processed excipient – LubriTose SD – Direct compression – Micromeritic evaluation.
Tablet is still the most frequently administered dosage form for medical applications. In the pharmaceutical industry, tablets are manufactured by three techniques: wet granulation, dry granulation and direct compression (DC). In granulation techniques, various processing steps and manufacturing challenges are involved, leading to higher cost and time of tablet production. The preferred tablet production method is direct tableting. DC tableting as a technique involves the compression of a dry blend of powders that comprises drugs and various excipients, which results in a number of benefits including time and cost savings [1]. With this formulation procedure, granulation is no longer necessary before tableting. In a word, the simplicity and cost-effectiveness of DC have positioned it as a preferred alternative. However, DC process is highly influenced by powder characteristics such as flowability and compressibility [2]. At the beginning, untreated excipients were applied for DC, such as powder cellulose or α-lactose-monohydrate. Then, the excipients were improved by using various manufacturing processes, such as spray drying (spray-dried lactose), or by using a special sieve fraction (lactose 100 mesh), but the improvement is limited and does not always provide the requisite performance for drugs in formulation and manufacture [3, 4]. Co-processed excipient is the next technological innovation for DC, which fulfills the increasing demand for multifunctional excipients for DC tableting [5]. Co-processed excipients are prepared by incorporating one excipient into the particle structure of another excipient using processes such as co-drying, hot-melt extrusion, freeze thawing, and co-precipitation [6]. In this co-processed technique, excipients interact at the sub-particle level, retain or improve the desired properties of excipients, enhancing functionality, masking the undesirable properties of the individual components [3]. The co-processed multifunctional excipients are introduced to achieve better characteristics and tableting properties, including high compatibility, high intrinsic flow, good lubricating efficiency, improved blending properties and good binding properties, than a single substance or the physical mixtures [7]. Several of these co-processed excipients have been launched onto the market and are commercially available, including Ludipress, Cellactose, Microlac, StarLac, and Prosolv. [8] LubriTose SD is a new co-processed excipient consisting of spraydried monohydrate lactose and distilled glyceryl monostearate (GMS) (96:4, w/w). It is specifically designed to eliminate the need of adding a
separated lubricant to a formulation to avoid the processing problems, such as product rejections, increasing tablet disintegration, tablet press speed limitations, typically caused by the lubricant magnesium stearate (Mg-St.). GMS was hypothesized to be melt to form a film which could encapsulate monohydrate lactose particles during high speed press, thus the lubricating effects occur. However, few reports on this issue were thorough and detailed, thus it was necessary to seek verification. Hence, in our study, the new excipient LubriTose SD was characterized, including the micromeritic properties and its function in DC. For comparison, a physical mixture of spray-dried lactose and Mg-St., wherein Mg-St. accounted for 1 % of total weight, was evaluated parallelly. As we know, the amount of Mg-St. in tablets is usually not more than 1 %, while glyceryl monostearate (GMS) is seldom used in tablets as lubricants. The aim of LubriTose SD is to replace the classical mixture of lactose and Mg-St. in ordinary tablets, so using lactose and Mg-St. (1 %) as the physical mixture could approach the real conditions.
I. Materials and methods 1. Materials
LubriTose SD (Kerry, Norwich, United States), spray-dried monohydrate lactose (FlowLac 100, Meggle AG, Wasserburg, Germany), magnesium stearate (Caelo GmbH, Hilden, Germany), cross-carmellose Sodium (FMC, Phila, PA, United States), mefenamic acid (Yuancheng, Hubei, China), piroxicam (Galaxy, Wuhan, China), simvastatin (Galaxy, Wuhan, China), ibuprofen (Xinyinghe, Wuhan, China), puerarin (Jiahe, Shanghai, China), breviscapine (Jiexiang, Sichuan, China), aspirin (Xinhua, Zibo, China), vitamin C (Welcome, Hebei, China), loratadine (Yuansheng, Shanghai, China), ophiopogon extract (self-prepared by China Pharmaceutical University). metformin hydrochloride (Hi-stone Pharmaceutical Co., Ltd, Changshu, China)
2. Methods
2.1. Micromeritic properties 2.1.1. Particle shape and size distribution The morphology of LubriTose SD was studied by a scanning electron microscope (Philips XL-30, Eindhoven, The Netherlands) after coating the samples with a thin layer of gold on a sputter coater. Size uniformity of the LubriTose SD was also determined. The method 562
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
2.1.4.3. Elastic recovery Heckel equation provides the information about compressibility (ability of material to undergo volume reduction under pressure), but the compactibility, i.e., the ability of material to yield and compact with adequate strength should also be ascertained. Elastic recovery (ER) was used as the representation in this study. ER refers to the elastic expansion due to the inner stress when the tablet was removed from the die hole. High ER is the negative performance, which could result in the laminating of the tablets. The tested powder was pressed to prepare tablets under a certain pressure after measuring the tablets thickness (H0), then, after relaxation for 24 h, the thickness of tablets was measured again and Ht. ER was calculated according to the following equation:
was to put the standard sieves together in a descending order agitating the sieves for 5 min. From the percentage weight of LubriTose SD powder on each sieve, the size uniformity was analyzed. 2.1.2. Hygroscopicity LubriTose SD was weighed precisely and put in different glass dryers with different relative humidity (32.8, 43.2, 54.4, 75.3, 84.3 %) at the room temperature for 7 days, then the moisture absorption percentage was calculated. 2.1.3. Flowability 2.1.3.1. Evaluation of angle of repose The angle of repose was determined according to the fixed-height funnel method on a Powder Integrative Characteristic Tester (BT-1000, Danodong Bettersize Instrument Co., Ltd., China). The corresponding physical blend was also measured as a reference. The experiment was repeated for each powder mixture in triplicate. If no special explanation is given, the following experiments were repeated in triplicate.
ER = [(Ht - H0)/H0] × 100 %
2.1.5. Dilution potential Dilution potential is the loading capacity of drug which an excipient can accommodate. The max amount of drug loaded was determined based on the following indices: appearance, weight variation, hardness, disintegration time, friability and in vitro drug release. Only when all the mentioned indices of the tablets were qualified could the index of dilution potential of a powder be approved. Several model drugs were selected as follows: ibuprofen, vitamin C and metformin hydrochloride (model drugs with poor flowability), aspirin and mefenamic acid (model drugs with poor compressibility), puerarin (model for traditional Chinese medicine), breviscapine (the traditional Chinese medicine with poor compressibility), ophiopogon extract (model for the traditional Chinese medicine with hygroscopicity).
2.1.3.2. Bulk density, tapped density and Carr’s index The bulk density and tapped density were also determined using a BT-1000 Powder Integrative Characteristic Tester. Carr’s index was calculated by terms of Equation 1: Carr’s index = (1 - bulk density/tapped density) × 100 %
Eq. 1
2.1.3.3. Flow velocity A certain weight of powder was poured into a glass funnel (50 mm diameter) and the bottom removed; the time taken for the sample to flow crossing the funnel was recorded. The flow rate of the powder was recorded in a ratio of mass (g) to time (s) (g/s).
2.2. Functionality Study 2.2.1. Effects on the flowability of drug LubriTose SD or its physical mixture was mixed with the model drug for 5 min. The flowability of powder blend was evaluated by angle of repose and Carr's index. Ibuprofen, aspirin and mefenamic acid were chosen in this study, with each drug loading determined in Section 1.5.
2.1.4. Compressibility analysis 2.1.4.1. Tensile strength under different pressure Tensile strength is an index of compression and compaction of the powder, which reflects the compaction of the powder; the higher the value, the better the compaction. The method to determine tensile strength was followed: after 24 h (time for stress relaxation) of compression, the crushing strength was determined using a hardness tester (78X-2B, Huanghai, China). From the values of the diameter d (cm), thickness h (cm), and the crushing strength fc (kg), the tensile strength sT (MPa) of the tablets was calculated using the following equation: sT = 2 fc/phd
2.2.2. Effects on the compressibility of drug LubriTose SD or the physical mixture was mixed with the model drug, ibuprofen or aspirin. Aspirin-loading in tablets was 50 %, ibuprofen loading was up to 80 %. The final powder blend was directly tableted on a Rimek Mini Press using a flat-faced 9 mm punch and die, with rotation speed at 15 rpm. The tensile strength of tablets under different pressure ranging from 5~20 KN was determined.
Eq. 2
2.1.4.2. Yield pressure The material property that predominantly affects the tableting of powders is the deformation behavior of powder under stress. The deformation characteristics may be elastic, plastic, brittle fracture or a combination of these deformation mechanisms. It is crucial to understand the particle deformation behavior and deformation kinetics, which will provide information about compressibility of powder. Heckel equation was used for the study. Powder (300 ± 5 mg) was compressed in a press (Rimek Mini Press-II SF, India) using a 9 mm flat-faced punch under the different pressure, and the tablets were stored in a sealed container for 24 h to ensure complete elastic recovery. Then, the tablet thickness (h) was measured with a micrometer, the thickness under the max pressure was marked as h0. The data were processed using the Heckel equation (Equation 3). The yield pressure (Py) from the reciprocal of the slope was obtained by regression analysis of the linear portion of the plot. Spray-dried monohydrate lactose was chosen as a reference: ln = 1/[1 - (h0/h)] = (1/Py) P + A
Eq. 4
2.2.3. Lubricating ability LubriTose SD was mixed with the model drug, ibuprofen, and the mixtures (ibuprofen accounted for 80 %) were tableted on a Rotary Tablet Press (Fette 2901, Germany). The ejection force of ibuprofen tablets under different pressures (5-12 kN) and different rotation speeds (15-35 rpm) were tested. 2.2.4. Stability studies Aspirin and Ophiopogon japonicus extract were sensitive to moisture and hence were chosen for this study. Drug loading was 50 and 30 %, respectively. The mixture of model drug and LubriTose SD was prepared into tablets, paralleling the physical mixture. Aspirin tablets were placed under a high temperature or a high humidity condition for 10 days, respectively. The content and related substances were determined at 0 and 10 days. Ophiopogon japonicus extract tablets were placed under different humidity conditions at room temperature; the equilibrium moisture content was tested.
Eq. 3 563
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
2.2.5. Effects on low-dose drugs content uniformity Piroxicam, loratadine and simvastatin were the low-dose drugs, and were chosen as models. After passing through 100-mesh sieve, the model drug was mixed with LubriTose SD or the physical mixture for 5 min in an Erweka multifunction instrument (AR402 Erweka, Germany), and pressed into tablets in a Rimek MiNi Press. The weight ratio of each model drug in tablet was 5 %. Ten pieces were selected at random and the content of each tablet was determined using HPLC [9-11]. The content uniformity was calculated in accordance with the provisions of the China Pharmacopoeia: determine separately the relative content X of each tablet which is expressed 100 as the labeled amount, calculate its mean value X, the standard deviation S and the absolute value A (A = |100 - X|), which is the difference between the labeled amount and the mean value; if A + 1.80S ≤ 15.0, the substance being examined complies with the test for content uniformity; if A + S > 15.0, the substance being examined fails to comply with the test for content uniformity; if A + 1.80S > 15.0, and A + S ≤ 15.0, then repeat the determination using another 20 tablets. According to the results of the first and repeated test, calculate the mean value X of 30 tablets, standard deviations S and the absolute value A, the difference between the labeled amount and the mean value; if A+1.45S ≤ 15.0, the substance being examined complies with the test for content uniformity; if A+1.45S > 15.0, the substance being examined fails to comply with the test for content uniformity.
Figure 1 - SEM of LubriTose SD. Table I - Results of particle size distribution of LubriTose SD. Sieve mesh
Particle size (µm)
Weight ratio (%)
< 50-mesh Between 50-65 mesh Between 65-80 mesh Between 80-100 mesh Between 100-250 mesh < 250-mesh
> 300 300-230 230-150 150-125 125-60 < 60
0.00 0.00 1.48 8.66 79.69 10.18
Table II - Flowability index of LubriTose SD and physical mixture (n = 3).
2.2.6. Effects on dissolution of poorly-soluble drugs In this study, the model drugs include mefenamic acid, piroxicam, simvastatin, ibuprofen, puerarin and breviscapine. All drugs passed through 80-mesh sieve, and mixed with LubriTose SD or the physical mixture. Also, 5 % cross-carmellose sodium was added as a disintegrant. The dissolution of the prepared tablets was performed according to the China Pharmacopoeia or the appropriate reference [12-15].
Angle of repose Bulk density (g/cm3) Tapped density (g/cm3) Carr’ index (%) Flow velocity (g/s)
LubriTose SD
Physical mixture
34.0 ± 0.6° 0.578 ± 0.007 0.687 ± 0.011 15.9 4.79 ± 0.09
39.4 ± 0.5° 0.631 ± 0.009 0.737 ± 0.012 14.4 2.50 ± 0.16
Thus, in aspects of all index, LubriTose SD showed good flowability, even better than spray-dried monohydrate lactose, which would be advantageous for DC. The better flowability of LubriTose SD may be attributed to the spherical shape and uniform size distribution.
II. Results and discussion 1. Micromeritic properties
1.1. Particle shape and size LubriTose SD showed a spherical shape and particle size of less than 150 μm as shown in Figure 1. Particle size uniformity test result based on sieving was shown in Table I. The particles between 60-125 μm were about 80 % of the total weight, which reflected the very superior size uniformity of LubriTose SD. The small and uniform size of LubriTose SD was good for flowability and compressibility.
1.4. Compressibility and compactibility analysis The tensile strength curves of LubriTose SD and the physical mixture were similar in Figure 2, which pointed to both excipients having the same compressibility. According to Figure 3, Py of LubriTose SD and spray-dried monohydrate lactose was 70.92 and 69.93 MPa, respectively, which implies LubriTose SD is in keeping with the deformation mechanism of spray-dried monohydrate lactose. Spray-dried lactose is produced by spray drying slurry containing lactose crystals. The final product contains a mixture of crystals of lactose monohydrate and spherical agglomerates of small crystals held
1.2. Hygroscopicity LubriTose SD showed very low hygroscopicity; even with relative humidity at 84 %, the average moisture amount was only 0.34 %. Therefore, LubriTose SD almost absorbed no moisture. 1.3. Flowability Three parameters were used to describe flowability: the angle of repose, Carr’s index, and flow rate. Angle of repose of LubriTose SD was 34.0 ± 0.6° (n = 3), better than the corresponding physical mixture (39.4 ± 0.5°, n = 3); this indicated the good flowability of the co-processed excipient. Carr’s index is also a parameter to reflect the powder flowability. Generally, a Carr’s index value between 5 and 15 % implies excellent flowability, which could meet powder DC need when using the rotary tableting machine. The Carr's index of LubriTose SD and the physical mixture sit exactly within this range (Table II), which implied both had good flowability. Flow velocity is also an important index. In general, the greater the flow rate, the better the flowability of powder. A poor flow velocity could cause significant differences to the tablet weight or content. Table II showed the physical mixture flowing fast, but LubriTose SD was faster, almost two times.
Tensile strength (MPa)
2 1.6 1.2 0.8 LubriTose SD 0.4
Physical mixture
0 5
10
15
20
25
Compression(kN)
Figure 2 - Tensile strength curve of LubriTose SD and its physical mixture. 564
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
of drugs. LubriTose SD was high for the drugs with good compressibility, but low for the poorly compressible drugs. Also, in our usual work, it was found that the dilution potential of LubriTose SD was high for the hydrophobic drug, while low for the hydrophilic drugs. The reasons were not clear, which may be due to water-soluble lactose in the LubriTose SD, which hampers the water-soluble drugs.
6
ln(1/(1-h/h0))
5 4 3 2
2. Functionality study
LubriTose SD
1
2.1. Improved flowability for drug The flowability index of model drugs with LubriTose SD or physical mixture are shown in Table III. All angles of repose of LubriTose SD groups were lower than the physical mixture groups, which meant LubriTose SD could improve the flowability of drug in DC. We also noticed the repose angles in Table III are a little higher, some above 40°; this may be due to the high drug loading, which was 80, 50 and 50 % for three drugs. Only Carr’s index of ibuprofen group was better than physical mixture, there was no obvious variation in the other two drugs. In a previous micromeritic study, LubriTose SD also had similar Carr’s index with physical mixture. The powder flowability can be assessed using different indices; each index reflects the flowability form’s different angle. In the present study, Carr's index cannot distinguish the flowability of LubriTose SD and its physical mixture. But the repose angle proved that LubriTose SD can improve the flowability of drugs in DC.
Spray dried monohydrate lactose
0 5
10
15
20
Compression(kN) Figure 3 - Heckel curve of LubriTose SD and spray dried monohydrate lactose. 10 8 6
ER(%) ı
LubriTose SD
physical mixture
4 2
2.2. Improved compressibility for drug The tensile strength of tablets made by the LubriTose SD group was higher than the physical mixture group under each compressive force (Figure 5). Based on the results, we argued that the co-processed excipient LubriTose SD resulted in improved compressibility of drugs, and often better than its physical mixture.
0 5
7
9
11
13
15
17
19
compression force(kN)
Figure 4 - Relationship of ER and pressure of LubriTose SD and physical mixture.
2.3. Lubricating ability A typical result is shown in Figure 6. It can be seen that the ejection force of the LubriTose SD group and the physical mixture group were close to each other, with both being lower than 250 N. In practice, an ejection force of lower than 400 N is acceptable in DC. We noticed the ejection force of the LubriTose SD group was slightly higher than the physical mixture group, but considering the exactly proportion of lubricant GMS in LubriTose SD, only 0.8 %, which was lower than Mg-St. (1 %) of the physical mixture, the above results could demonstrate the good lubricate ability of the LubriTose SD.
together by glass or amorphous material. Crystalline lactose mainly consolidates by fragmentation and amorphous lactose by plastic deformation [16]. Therefore, LubriTose SD should be consolidated by both plastic deformation and fragmentation. In Figure 4, LubriTose SD and the physical mixture showed very low ER, which meant both had good compactibility. Summing up the above results, we could conclude the LubriTose SD and spray-dried monohydrate lactose have the same deformation mechanisms, a combination of plastic and brittle deformation. At the same time, LubriTose SD had the similar compressibility and compactibility with the physical mixture.
2.4. Stability studies As shown in Table IV, after high temperature condition for 10 days, the aspirin content in two groups was essentially the same as the beginning, but the related substances exceeded the limitation in the physical mixture group, as they also did in the high humidity condition. The above results showed that LubriTose SD may favor the stability of moisture-sensitive drugs. Ophiopogon japonicus extracts tended to absorb moisture. We found that in various humidity conditions, the equilibrium moisture content of the two groups was basically the same, but the LubriTose SD group was lower in RH 92.5 %. All in all, LubriTose SD was slightly better than the physical
1.5. Dilution potential The dilution potential is the amount of poorly compressible drug that can be satisfactorily compressed into a tablet with a directly compressible excipient [17]. When all the tested indices were qualified, the max amount of drug loading was as follows: ibuprofen could reach to 80 %, puerarin was up to 60 %, mefenamic acid, aspirin, and breviscapine were all up to 50 %, even the highly hygroscopic ophiopogon extract could easily reach to 30 %, however, vitamin C was only up to 10 %, and metformin hydrochloride group was not smoothly tableted. Dilution potential reflects the improvement for the compressibility
Table III - Flowability parameter of model drug and LubriTose SD or its physical mixture (n = 3). Ibuprofen Angle of repose Bulk density (g/cm3) Tapping density (g/cm3) Carr’s index (%)
Aspirin
Mefenamic acid
LubriTose
Physical mixture
LubriTose
Physical mixture
LubriTose
Physical mixture
40.1 ± 0.2° 0.430 ± 0.006 0.546 ± 0.013 21.2
45.8 ± 0.4° 0.437 ± 0.008 0.615 ± 0.008 28.9
38.1 ± 0.4° 0.557 ± 0.011 0.717 ± 0.010 22.3
41.4 ± 0.3° 0.601 ± 0.007 0.773 ± 0.015 22.3
43.0 ± 0.5° 0.507 ± 0.012 0.692 ± 0.009 26.8
47.6 ± 0.5° 0.511 ± 0.009 0.708 ± 0.013 27.9
565
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
Table V - The content uniformity of low dose drugs (n = 10).
1.6
1.6
tensile strengh9MPa)
tensile strength(MPa)
2
1.2 0.8 Aspirin + LubriTose SD
0.4
Aspirin + physical mixture
0
5
10
15
20
25
1.0
Ibuprofen + LubriTose SD
0.8 4
compression (kN)
6
8
10
12
compression force (kN)
Qualified Qualified
Loratadine LT Loratadine PM
98.76 102.5
7.89 10.54
Qualified Qualified
Simvastatin LT Simvastatin PM
104.2 104.5
7.54 9.38
Qualified Qualified
also sit in this range, both of which would minimize the segregation potential. These may contribute to the qualified content uniformity. 2.6. Effects on dissolution of poorly soluble drugs The dissolution results of model drugs are shown in Table VI. As can be seen, the accumulated drug release percentage of the two groups has no significant difference, the dissolution of LubriTose SD group was similar to the physical mixture group, which implies the contained and binded GMS has no negative effects on disintegration and dissolution of tablets.
300 250
Ejection force(N)
Conclusions
4.27 8.25
14
Figure 5 - Tensile strength curves of aspirin and ibuprofen tablets.
200 150 100
Ibuprofen + LubriTose SD
*
Ibuprofen + physical mixture
50
The present study examined a new co-processed excipient, LubriTose SD integrated GMS with monohydrate lactose. According to all the results, the new materials show a series of advantages when compared to the corresponding physical mixture. First, spherical and uniform LubriTose SD has superior flowability, even better than the spray-dried monohydrate lactose, which makes it especially useful in powder direct compression. Second, the compressibility of LubriTose SD is in accordance with spray-dried monohydrate lactose. However, it indeed improves the compressibility of drug in under direct compression, which can be seen from the increasing tensile strength. Preliminary speculation is due to the role of GMS during tableting. GMS has a lower melting point than Mg-St., so the molten bridge of GMS during high speed compression will make more particles bind to improve the compressibility. Third, compared with the excellent lubricating ability of Mg-St., our study proves that LubriTose SD is no worse than Mg-St. Moreover, the self-lubricating ability of LubriTose SD means there is no need to add Mg-St. in powder direct compression, which can reduce or eliminate tableting problems typically encountered when using Mg-St. as a lubricant, for example, mixing uniformity, hardness and dissolution decreases due to the Mg-St. hydrophobic film on the surface of tablets. In addition, with LubriTose SD due to be bound with lubricant GMS, not adding Mg-St. will be of benefit by simplifying the formulation screening, shortening investigation cycle, reducing resources in management, such as purchasing, tests and stockpile, all of which are of importance for improving and promoting tablet manufacturing enterprise. Other advantages of LubriTose SD include: high loading capacity to hydrophobic drugs, good content uniformity for low-dose drug in direct compression process (helpful to the hygroscopicity stability for moisture-sensitive drugs); no negative effects on the disintegration and dissolution of tablets; and the fact that often LubriTose SD performed slightly better than its corresponding physical mixture.
0 4
6
8
10
12
Compression(kN)
Figure 6 - Ejection force curve of ibuprofen tablets at 25rpm. Table IV - The stability results of aspirin tablets. 0 day
LT PM
A+1.80S
100.4 101.2
1.2
Ibuprofen + physical mixture
0
Content (%) Piroxicam LT Piroxicam PM
1.4
60 °C, 10 days
RH 92.5 %, 10 days
Cont. (%)
RS (%)
Cont. (%)
RS (%)
Cont. (%)
RS (%)
100.0 100.0
0.14 0.19
100.2 101.6
0.07 0.36
103.4 97.2
0.20 0.45
In accordance with the provisions of China Pharmacopoeia, the related substances of aspirin should not exceed 0.3 %. RS = related substances.
mixture on improving the hygroscopic drugs stability, which may contribute to the very low moisture absorption of LubriTose SD. 2.5. Effects on low dose drugs content uniformity The tablets’ content uniformity of three drugs is shown in Table V. According to Chinese Pharmacopoeia, when A + 1.8S < 15, it notes the qualified uniformity, among which, S is standard deviation of content, and A is the absolute value of the difference between 100 and average content. Both groups were qualified. It was argued that LubriTose SD had no negative effects on the content uniformity of low dose drugs, and even performed better than the physical mixture. Similarly with spray-dried lactose, LubriTose SD had perfect flowability, which can be seen from the low angle of repose and high flow velocity. Good flowability would reduce tablet weight variation and improve content uniformity. In addition, LubriTose SD had a very narrow size distribution, from 60 to 150 μm. The size of the model drugs after 100-mesh sieving Table VI - The dissolution results of model drugs (n = 6).
Average disolution (%) LT PM
Mefenamic acid
Piroxicam
Simvastatin
Ibuprofen
Puerarin
Breviscapine
93.49 ± 0.95 91.45 ± 1.25
96.22 ± 0.99 93.2 ± 0.93
96.87 ± 1.23 102.31 ± 0.76
92.96 ± 1.75 91.10 ± 0.89
95.46 ± 0.68 93.76 ± 1.43
61.37 ± 2.87 62.86 ± 3.15
566
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
In summary, it was demonstrated that using of GMS in a DC tableting could fulfill the lubricant role successfully. LubriTose SD is a co-processed material with self-lubricating properties; it is promisingly suitable for oral solid formulation of hydrophobic drugs, such as powder direct compression.
9. 10.
References 1. 2. 3.
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Gohel M.C., Jogani P.D. - A review of co-processed directly compressible excipients. - J. Pharm. Pharmaceut. Sci., 8, 7693, 2005. Jivraj M., Martini L.G., Thomson C.M. - An overview of the different excipients useful for the direct compression of tablets. - Pharmaceutical Science & Technology Today, 3, 58-63, 2000. Block L.H., Moreton R.C., Apte S.P., Wendt R.H., Munson E.J., Creekmore J.R., Persaud I.V., Sheehan C, Wang H. - Coprocessed excipients. - Pharmacopeial Forum , 35, 1026-1028, 2009. Limwong V., Sutanthavibul N., Kulvanich P. - Spherical composite particles of rice starch and microcrystalline cellulose: a new coprocessed excipient for direct compression. - AAPS PharmSciTech, 5, e30, 2004. Hauschild K., Picker K.M. - Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formulation. - AAPS PharmSci, 6, Article 16, 2004. Mirani A.G., Patankar S.P., Borole V.S., Pawar A.S., Kadam V.J. - Direct compression high functionality excipient using coprocessing technique: a brief review. - Current Drug Delivery, 8, 426-435, 2011. Ogunjimi A.T., Alebiowu G. - A quantitative study of the influence of co processing of binders on the mechanical properties of paracetamol tablets. - Brazilian Journal of Pharmaceutical Sciences, 46, 205-212, 2010. Olowosulu A.K., Avosuahi O, Isah A.B., Ibrahim M.A. - Formulation and evaluation of novel coprocessed excipients of maize starch and acacia gum (StarAc) for direct compression
12. 13. 14.
15. 16. 17.
tabletting. - International Journal of Pharmaceutical Research and Innovation, 2, 39-45, 2011. Chen X., Zhang Q. -Study on the of dissolution rate of piroxicam in entecavir capsules. - Strait Pharmaceutical Journal, 22, 4445, 2010. Cho C.W., Choi J.S., Kin S.J., Shin S.C. - Enhanced bioavailability and antihistamine of loratadine from the transdermal EVA matrix system in rats. - J. Drug Del. Sci. Tech., 20, 107-110, 2010. Ungaro F., Giovino C., Catanzano O., Miro A., Mele A., Quaglia F., Rotonda M.I.L. - Use of cyclodextrins as solubilizing agents for simvastatin: effect of hydroxypropyl-β-cyclodextrin on lactone/ hydroxyacid aqueous equilibrium. - Int. J. Pharm., 404,49–56, 2011. Güngör S., Yıldız A., Özsoy Y., Cevher E., Araman A. - Investigations on mefenamic acid sustained release tablets with water-insoluble gel. - Il Farmaco, 58, 397-401, 2003. Wang Q., Cui L. - Improving dissolution properties and masking bitterness of ibuprofen by hot-melt extrusion. - Pharm Care Res., 12, 123-125, 2012. Han L.W., Zhang G.Y., Gong W.H., Han Z.D. - Preparation and in vitro evaluation of puerarin polyvinylpyrrolidone K30 solid dispersions. - Chinese Journal of Experimental Traditional Medical Formulae, 17, 1-4, 2011. Zhou Y.S., Zhai D.Y., Duan Q.H., Qin M.S. - The formula of breviscapine oral disintegrating tablets and its preparation. Chinese Traditional Patent Medicine, 28, 941-944, 2006. Ahjel S.W., Lupuliasa D. - Directly compressible adjuvants-a pharmaceutical approach. - Farmacia, 6, 591-599, 2008. Patel S.S., Patel N.M. - Development of directly compressible coprocessed excipient for dispersible tablets using 32 full factorial design.- International Journal of Pharmacy and Pharmaceutical Sciences, 1, 125-148, 2009.
Manuscript Received 14 May 2012, accepted for publication 20 July 2012.
567
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian1, C. Tian2, X. Ke2* Pharmacy Experimental Center, 2Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China *Correspondence: [email protected]
1
LubriTose SD is a new co-processed excipient consisting of spray-dried monohydrate lactose and distilled glyceryl monostearate. In this study, the new self-lubricating excipient LubriTose SD was characterized from the aspects of powder technological properties and tableting properties. Micromeritic properties, including particle shape, size distribution, flowability, compressibility, and also the dilution potential were determined. Its applications in powder direct compression have been evaluated, including the effects on flowability, compressibility, the lubricating ability, hygroscopic drugs stability, content uniformity of the low-dose drugs and dissolution of poorly soluble drugs. LubriTose SD is 100 μm with very uniform size distribution and with spherical shape, shows the best flowability, has the same deformation mechanism with the spray-dried monohydrate lactose, has high dilution potential to the hydrophobic drug and has improved function of drug tableting. Its lubricating effect is satisfactory. The results of the investigation imply that the LubriTose SD is a good co-processed excipient with self-lubricating properties, which is promisingly suitable for powder direct compression. Key words: Co-processed excipient – LubriTose SD – Direct compression – Micromeritic evaluation.
Tablet is still the most frequently administered dosage form for medical applications. In the pharmaceutical industry, tablets are manufactured by three techniques: wet granulation, dry granulation and direct compression (DC). In granulation techniques, various processing steps and manufacturing challenges are involved, leading to higher cost and time of tablet production. The preferred tablet production method is direct tableting. DC tableting as a technique involves the compression of a dry blend of powders that comprises drugs and various excipients, which results in a number of benefits including time and cost savings [1]. With this formulation procedure, granulation is no longer necessary before tableting. In a word, the simplicity and cost-effectiveness of DC have positioned it as a preferred alternative. However, DC process is highly influenced by powder characteristics such as flowability and compressibility [2]. At the beginning, untreated excipients were applied for DC, such as powder cellulose or α-lactose-monohydrate. Then, the excipients were improved by using various manufacturing processes, such as spray drying (spray-dried lactose), or by using a special sieve fraction (lactose 100 mesh), but the improvement is limited and does not always provide the requisite performance for drugs in formulation and manufacture [3, 4]. Co-processed excipient is the next technological innovation for DC, which fulfills the increasing demand for multifunctional excipients for DC tableting [5]. Co-processed excipients are prepared by incorporating one excipient into the particle structure of another excipient using processes such as co-drying, hot-melt extrusion, freeze thawing, and co-precipitation [6]. In this co-processed technique, excipients interact at the sub-particle level, retain or improve the desired properties of excipients, enhancing functionality, masking the undesirable properties of the individual components [3]. The co-processed multifunctional excipients are introduced to achieve better characteristics and tableting properties, including high compatibility, high intrinsic flow, good lubricating efficiency, improved blending properties and good binding properties, than a single substance or the physical mixtures [7]. Several of these co-processed excipients have been launched onto the market and are commercially available, including Ludipress, Cellactose, Microlac, StarLac, and Prosolv. [8] LubriTose SD is a new co-processed excipient consisting of spraydried monohydrate lactose and distilled glyceryl monostearate (GMS) (96:4, w/w). It is specifically designed to eliminate the need of adding a
separated lubricant to a formulation to avoid the processing problems, such as product rejections, increasing tablet disintegration, tablet press speed limitations, typically caused by the lubricant magnesium stearate (Mg-St.). GMS was hypothesized to be melt to form a film which could encapsulate monohydrate lactose particles during high speed press, thus the lubricating effects occur. However, few reports on this issue were thorough and detailed, thus it was necessary to seek verification. Hence, in our study, the new excipient LubriTose SD was characterized, including the micromeritic properties and its function in DC. For comparison, a physical mixture of spray-dried lactose and Mg-St., wherein Mg-St. accounted for 1 % of total weight, was evaluated parallelly. As we know, the amount of Mg-St. in tablets is usually not more than 1 %, while glyceryl monostearate (GMS) is seldom used in tablets as lubricants. The aim of LubriTose SD is to replace the classical mixture of lactose and Mg-St. in ordinary tablets, so using lactose and Mg-St. (1 %) as the physical mixture could approach the real conditions.
I. Materials and methods 1. Materials
LubriTose SD (Kerry, Norwich, United States), spray-dried monohydrate lactose (FlowLac 100, Meggle AG, Wasserburg, Germany), magnesium stearate (Caelo GmbH, Hilden, Germany), cross-carmellose Sodium (FMC, Phila, PA, United States), mefenamic acid (Yuancheng, Hubei, China), piroxicam (Galaxy, Wuhan, China), simvastatin (Galaxy, Wuhan, China), ibuprofen (Xinyinghe, Wuhan, China), puerarin (Jiahe, Shanghai, China), breviscapine (Jiexiang, Sichuan, China), aspirin (Xinhua, Zibo, China), vitamin C (Welcome, Hebei, China), loratadine (Yuansheng, Shanghai, China), ophiopogon extract (self-prepared by China Pharmaceutical University). metformin hydrochloride (Hi-stone Pharmaceutical Co., Ltd, Changshu, China)
2. Methods
2.1. Micromeritic properties 2.1.1. Particle shape and size distribution The morphology of LubriTose SD was studied by a scanning electron microscope (Philips XL-30, Eindhoven, The Netherlands) after coating the samples with a thin layer of gold on a sputter coater. Size uniformity of the LubriTose SD was also determined. The method 562
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
2.1.4.3. Elastic recovery Heckel equation provides the information about compressibility (ability of material to undergo volume reduction under pressure), but the compactibility, i.e., the ability of material to yield and compact with adequate strength should also be ascertained. Elastic recovery (ER) was used as the representation in this study. ER refers to the elastic expansion due to the inner stress when the tablet was removed from the die hole. High ER is the negative performance, which could result in the laminating of the tablets. The tested powder was pressed to prepare tablets under a certain pressure after measuring the tablets thickness (H0), then, after relaxation for 24 h, the thickness of tablets was measured again and Ht. ER was calculated according to the following equation:
was to put the standard sieves together in a descending order agitating the sieves for 5 min. From the percentage weight of LubriTose SD powder on each sieve, the size uniformity was analyzed. 2.1.2. Hygroscopicity LubriTose SD was weighed precisely and put in different glass dryers with different relative humidity (32.8, 43.2, 54.4, 75.3, 84.3 %) at the room temperature for 7 days, then the moisture absorption percentage was calculated. 2.1.3. Flowability 2.1.3.1. Evaluation of angle of repose The angle of repose was determined according to the fixed-height funnel method on a Powder Integrative Characteristic Tester (BT-1000, Danodong Bettersize Instrument Co., Ltd., China). The corresponding physical blend was also measured as a reference. The experiment was repeated for each powder mixture in triplicate. If no special explanation is given, the following experiments were repeated in triplicate.
ER = [(Ht - H0)/H0] × 100 %
2.1.5. Dilution potential Dilution potential is the loading capacity of drug which an excipient can accommodate. The max amount of drug loaded was determined based on the following indices: appearance, weight variation, hardness, disintegration time, friability and in vitro drug release. Only when all the mentioned indices of the tablets were qualified could the index of dilution potential of a powder be approved. Several model drugs were selected as follows: ibuprofen, vitamin C and metformin hydrochloride (model drugs with poor flowability), aspirin and mefenamic acid (model drugs with poor compressibility), puerarin (model for traditional Chinese medicine), breviscapine (the traditional Chinese medicine with poor compressibility), ophiopogon extract (model for the traditional Chinese medicine with hygroscopicity).
2.1.3.2. Bulk density, tapped density and Carr’s index The bulk density and tapped density were also determined using a BT-1000 Powder Integrative Characteristic Tester. Carr’s index was calculated by terms of Equation 1: Carr’s index = (1 - bulk density/tapped density) × 100 %
Eq. 1
2.1.3.3. Flow velocity A certain weight of powder was poured into a glass funnel (50 mm diameter) and the bottom removed; the time taken for the sample to flow crossing the funnel was recorded. The flow rate of the powder was recorded in a ratio of mass (g) to time (s) (g/s).
2.2. Functionality Study 2.2.1. Effects on the flowability of drug LubriTose SD or its physical mixture was mixed with the model drug for 5 min. The flowability of powder blend was evaluated by angle of repose and Carr's index. Ibuprofen, aspirin and mefenamic acid were chosen in this study, with each drug loading determined in Section 1.5.
2.1.4. Compressibility analysis 2.1.4.1. Tensile strength under different pressure Tensile strength is an index of compression and compaction of the powder, which reflects the compaction of the powder; the higher the value, the better the compaction. The method to determine tensile strength was followed: after 24 h (time for stress relaxation) of compression, the crushing strength was determined using a hardness tester (78X-2B, Huanghai, China). From the values of the diameter d (cm), thickness h (cm), and the crushing strength fc (kg), the tensile strength sT (MPa) of the tablets was calculated using the following equation: sT = 2 fc/phd
2.2.2. Effects on the compressibility of drug LubriTose SD or the physical mixture was mixed with the model drug, ibuprofen or aspirin. Aspirin-loading in tablets was 50 %, ibuprofen loading was up to 80 %. The final powder blend was directly tableted on a Rimek Mini Press using a flat-faced 9 mm punch and die, with rotation speed at 15 rpm. The tensile strength of tablets under different pressure ranging from 5~20 KN was determined.
Eq. 2
2.1.4.2. Yield pressure The material property that predominantly affects the tableting of powders is the deformation behavior of powder under stress. The deformation characteristics may be elastic, plastic, brittle fracture or a combination of these deformation mechanisms. It is crucial to understand the particle deformation behavior and deformation kinetics, which will provide information about compressibility of powder. Heckel equation was used for the study. Powder (300 ± 5 mg) was compressed in a press (Rimek Mini Press-II SF, India) using a 9 mm flat-faced punch under the different pressure, and the tablets were stored in a sealed container for 24 h to ensure complete elastic recovery. Then, the tablet thickness (h) was measured with a micrometer, the thickness under the max pressure was marked as h0. The data were processed using the Heckel equation (Equation 3). The yield pressure (Py) from the reciprocal of the slope was obtained by regression analysis of the linear portion of the plot. Spray-dried monohydrate lactose was chosen as a reference: ln = 1/[1 - (h0/h)] = (1/Py) P + A
Eq. 4
2.2.3. Lubricating ability LubriTose SD was mixed with the model drug, ibuprofen, and the mixtures (ibuprofen accounted for 80 %) were tableted on a Rotary Tablet Press (Fette 2901, Germany). The ejection force of ibuprofen tablets under different pressures (5-12 kN) and different rotation speeds (15-35 rpm) were tested. 2.2.4. Stability studies Aspirin and Ophiopogon japonicus extract were sensitive to moisture and hence were chosen for this study. Drug loading was 50 and 30 %, respectively. The mixture of model drug and LubriTose SD was prepared into tablets, paralleling the physical mixture. Aspirin tablets were placed under a high temperature or a high humidity condition for 10 days, respectively. The content and related substances were determined at 0 and 10 days. Ophiopogon japonicus extract tablets were placed under different humidity conditions at room temperature; the equilibrium moisture content was tested.
Eq. 3 563
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
2.2.5. Effects on low-dose drugs content uniformity Piroxicam, loratadine and simvastatin were the low-dose drugs, and were chosen as models. After passing through 100-mesh sieve, the model drug was mixed with LubriTose SD or the physical mixture for 5 min in an Erweka multifunction instrument (AR402 Erweka, Germany), and pressed into tablets in a Rimek MiNi Press. The weight ratio of each model drug in tablet was 5 %. Ten pieces were selected at random and the content of each tablet was determined using HPLC [9-11]. The content uniformity was calculated in accordance with the provisions of the China Pharmacopoeia: determine separately the relative content X of each tablet which is expressed 100 as the labeled amount, calculate its mean value X, the standard deviation S and the absolute value A (A = |100 - X|), which is the difference between the labeled amount and the mean value; if A + 1.80S ≤ 15.0, the substance being examined complies with the test for content uniformity; if A + S > 15.0, the substance being examined fails to comply with the test for content uniformity; if A + 1.80S > 15.0, and A + S ≤ 15.0, then repeat the determination using another 20 tablets. According to the results of the first and repeated test, calculate the mean value X of 30 tablets, standard deviations S and the absolute value A, the difference between the labeled amount and the mean value; if A+1.45S ≤ 15.0, the substance being examined complies with the test for content uniformity; if A+1.45S > 15.0, the substance being examined fails to comply with the test for content uniformity.
Figure 1 - SEM of LubriTose SD. Table I - Results of particle size distribution of LubriTose SD. Sieve mesh
Particle size (µm)
Weight ratio (%)
< 50-mesh Between 50-65 mesh Between 65-80 mesh Between 80-100 mesh Between 100-250 mesh < 250-mesh
> 300 300-230 230-150 150-125 125-60 < 60
0.00 0.00 1.48 8.66 79.69 10.18
Table II - Flowability index of LubriTose SD and physical mixture (n = 3).
2.2.6. Effects on dissolution of poorly-soluble drugs In this study, the model drugs include mefenamic acid, piroxicam, simvastatin, ibuprofen, puerarin and breviscapine. All drugs passed through 80-mesh sieve, and mixed with LubriTose SD or the physical mixture. Also, 5 % cross-carmellose sodium was added as a disintegrant. The dissolution of the prepared tablets was performed according to the China Pharmacopoeia or the appropriate reference [12-15].
Angle of repose Bulk density (g/cm3) Tapped density (g/cm3) Carr’ index (%) Flow velocity (g/s)
LubriTose SD
Physical mixture
34.0 ± 0.6° 0.578 ± 0.007 0.687 ± 0.011 15.9 4.79 ± 0.09
39.4 ± 0.5° 0.631 ± 0.009 0.737 ± 0.012 14.4 2.50 ± 0.16
Thus, in aspects of all index, LubriTose SD showed good flowability, even better than spray-dried monohydrate lactose, which would be advantageous for DC. The better flowability of LubriTose SD may be attributed to the spherical shape and uniform size distribution.
II. Results and discussion 1. Micromeritic properties
1.1. Particle shape and size LubriTose SD showed a spherical shape and particle size of less than 150 μm as shown in Figure 1. Particle size uniformity test result based on sieving was shown in Table I. The particles between 60-125 μm were about 80 % of the total weight, which reflected the very superior size uniformity of LubriTose SD. The small and uniform size of LubriTose SD was good for flowability and compressibility.
1.4. Compressibility and compactibility analysis The tensile strength curves of LubriTose SD and the physical mixture were similar in Figure 2, which pointed to both excipients having the same compressibility. According to Figure 3, Py of LubriTose SD and spray-dried monohydrate lactose was 70.92 and 69.93 MPa, respectively, which implies LubriTose SD is in keeping with the deformation mechanism of spray-dried monohydrate lactose. Spray-dried lactose is produced by spray drying slurry containing lactose crystals. The final product contains a mixture of crystals of lactose monohydrate and spherical agglomerates of small crystals held
1.2. Hygroscopicity LubriTose SD showed very low hygroscopicity; even with relative humidity at 84 %, the average moisture amount was only 0.34 %. Therefore, LubriTose SD almost absorbed no moisture. 1.3. Flowability Three parameters were used to describe flowability: the angle of repose, Carr’s index, and flow rate. Angle of repose of LubriTose SD was 34.0 ± 0.6° (n = 3), better than the corresponding physical mixture (39.4 ± 0.5°, n = 3); this indicated the good flowability of the co-processed excipient. Carr’s index is also a parameter to reflect the powder flowability. Generally, a Carr’s index value between 5 and 15 % implies excellent flowability, which could meet powder DC need when using the rotary tableting machine. The Carr's index of LubriTose SD and the physical mixture sit exactly within this range (Table II), which implied both had good flowability. Flow velocity is also an important index. In general, the greater the flow rate, the better the flowability of powder. A poor flow velocity could cause significant differences to the tablet weight or content. Table II showed the physical mixture flowing fast, but LubriTose SD was faster, almost two times.
Tensile strength (MPa)
2 1.6 1.2 0.8 LubriTose SD 0.4
Physical mixture
0 5
10
15
20
25
Compression(kN)
Figure 2 - Tensile strength curve of LubriTose SD and its physical mixture. 564
Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
of drugs. LubriTose SD was high for the drugs with good compressibility, but low for the poorly compressible drugs. Also, in our usual work, it was found that the dilution potential of LubriTose SD was high for the hydrophobic drug, while low for the hydrophilic drugs. The reasons were not clear, which may be due to water-soluble lactose in the LubriTose SD, which hampers the water-soluble drugs.
6
ln(1/(1-h/h0))
5 4 3 2
2. Functionality study
LubriTose SD
1
2.1. Improved flowability for drug The flowability index of model drugs with LubriTose SD or physical mixture are shown in Table III. All angles of repose of LubriTose SD groups were lower than the physical mixture groups, which meant LubriTose SD could improve the flowability of drug in DC. We also noticed the repose angles in Table III are a little higher, some above 40°; this may be due to the high drug loading, which was 80, 50 and 50 % for three drugs. Only Carr’s index of ibuprofen group was better than physical mixture, there was no obvious variation in the other two drugs. In a previous micromeritic study, LubriTose SD also had similar Carr’s index with physical mixture. The powder flowability can be assessed using different indices; each index reflects the flowability form’s different angle. In the present study, Carr's index cannot distinguish the flowability of LubriTose SD and its physical mixture. But the repose angle proved that LubriTose SD can improve the flowability of drugs in DC.
Spray dried monohydrate lactose
0 5
10
15
20
Compression(kN) Figure 3 - Heckel curve of LubriTose SD and spray dried monohydrate lactose. 10 8 6
ER(%) ı
LubriTose SD
physical mixture
4 2
2.2. Improved compressibility for drug The tensile strength of tablets made by the LubriTose SD group was higher than the physical mixture group under each compressive force (Figure 5). Based on the results, we argued that the co-processed excipient LubriTose SD resulted in improved compressibility of drugs, and often better than its physical mixture.
0 5
7
9
11
13
15
17
19
compression force(kN)
Figure 4 - Relationship of ER and pressure of LubriTose SD and physical mixture.
2.3. Lubricating ability A typical result is shown in Figure 6. It can be seen that the ejection force of the LubriTose SD group and the physical mixture group were close to each other, with both being lower than 250 N. In practice, an ejection force of lower than 400 N is acceptable in DC. We noticed the ejection force of the LubriTose SD group was slightly higher than the physical mixture group, but considering the exactly proportion of lubricant GMS in LubriTose SD, only 0.8 %, which was lower than Mg-St. (1 %) of the physical mixture, the above results could demonstrate the good lubricate ability of the LubriTose SD.
together by glass or amorphous material. Crystalline lactose mainly consolidates by fragmentation and amorphous lactose by plastic deformation [16]. Therefore, LubriTose SD should be consolidated by both plastic deformation and fragmentation. In Figure 4, LubriTose SD and the physical mixture showed very low ER, which meant both had good compactibility. Summing up the above results, we could conclude the LubriTose SD and spray-dried monohydrate lactose have the same deformation mechanisms, a combination of plastic and brittle deformation. At the same time, LubriTose SD had the similar compressibility and compactibility with the physical mixture.
2.4. Stability studies As shown in Table IV, after high temperature condition for 10 days, the aspirin content in two groups was essentially the same as the beginning, but the related substances exceeded the limitation in the physical mixture group, as they also did in the high humidity condition. The above results showed that LubriTose SD may favor the stability of moisture-sensitive drugs. Ophiopogon japonicus extracts tended to absorb moisture. We found that in various humidity conditions, the equilibrium moisture content of the two groups was basically the same, but the LubriTose SD group was lower in RH 92.5 %. All in all, LubriTose SD was slightly better than the physical
1.5. Dilution potential The dilution potential is the amount of poorly compressible drug that can be satisfactorily compressed into a tablet with a directly compressible excipient [17]. When all the tested indices were qualified, the max amount of drug loading was as follows: ibuprofen could reach to 80 %, puerarin was up to 60 %, mefenamic acid, aspirin, and breviscapine were all up to 50 %, even the highly hygroscopic ophiopogon extract could easily reach to 30 %, however, vitamin C was only up to 10 %, and metformin hydrochloride group was not smoothly tableted. Dilution potential reflects the improvement for the compressibility
Table III - Flowability parameter of model drug and LubriTose SD or its physical mixture (n = 3). Ibuprofen Angle of repose Bulk density (g/cm3) Tapping density (g/cm3) Carr’s index (%)
Aspirin
Mefenamic acid
LubriTose
Physical mixture
LubriTose
Physical mixture
LubriTose
Physical mixture
40.1 ± 0.2° 0.430 ± 0.006 0.546 ± 0.013 21.2
45.8 ± 0.4° 0.437 ± 0.008 0.615 ± 0.008 28.9
38.1 ± 0.4° 0.557 ± 0.011 0.717 ± 0.010 22.3
41.4 ± 0.3° 0.601 ± 0.007 0.773 ± 0.015 22.3
43.0 ± 0.5° 0.507 ± 0.012 0.692 ± 0.009 26.8
47.6 ± 0.5° 0.511 ± 0.009 0.708 ± 0.013 27.9
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Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
Table V - The content uniformity of low dose drugs (n = 10).
1.6
1.6
tensile strengh9MPa)
tensile strength(MPa)
2
1.2 0.8 Aspirin + LubriTose SD
0.4
Aspirin + physical mixture
0
5
10
15
20
25
1.0
Ibuprofen + LubriTose SD
0.8 4
compression (kN)
6
8
10
12
compression force (kN)
Qualified Qualified
Loratadine LT Loratadine PM
98.76 102.5
7.89 10.54
Qualified Qualified
Simvastatin LT Simvastatin PM
104.2 104.5
7.54 9.38
Qualified Qualified
also sit in this range, both of which would minimize the segregation potential. These may contribute to the qualified content uniformity. 2.6. Effects on dissolution of poorly soluble drugs The dissolution results of model drugs are shown in Table VI. As can be seen, the accumulated drug release percentage of the two groups has no significant difference, the dissolution of LubriTose SD group was similar to the physical mixture group, which implies the contained and binded GMS has no negative effects on disintegration and dissolution of tablets.
300 250
Ejection force(N)
Conclusions
4.27 8.25
14
Figure 5 - Tensile strength curves of aspirin and ibuprofen tablets.
200 150 100
Ibuprofen + LubriTose SD
*
Ibuprofen + physical mixture
50
The present study examined a new co-processed excipient, LubriTose SD integrated GMS with monohydrate lactose. According to all the results, the new materials show a series of advantages when compared to the corresponding physical mixture. First, spherical and uniform LubriTose SD has superior flowability, even better than the spray-dried monohydrate lactose, which makes it especially useful in powder direct compression. Second, the compressibility of LubriTose SD is in accordance with spray-dried monohydrate lactose. However, it indeed improves the compressibility of drug in under direct compression, which can be seen from the increasing tensile strength. Preliminary speculation is due to the role of GMS during tableting. GMS has a lower melting point than Mg-St., so the molten bridge of GMS during high speed compression will make more particles bind to improve the compressibility. Third, compared with the excellent lubricating ability of Mg-St., our study proves that LubriTose SD is no worse than Mg-St. Moreover, the self-lubricating ability of LubriTose SD means there is no need to add Mg-St. in powder direct compression, which can reduce or eliminate tableting problems typically encountered when using Mg-St. as a lubricant, for example, mixing uniformity, hardness and dissolution decreases due to the Mg-St. hydrophobic film on the surface of tablets. In addition, with LubriTose SD due to be bound with lubricant GMS, not adding Mg-St. will be of benefit by simplifying the formulation screening, shortening investigation cycle, reducing resources in management, such as purchasing, tests and stockpile, all of which are of importance for improving and promoting tablet manufacturing enterprise. Other advantages of LubriTose SD include: high loading capacity to hydrophobic drugs, good content uniformity for low-dose drug in direct compression process (helpful to the hygroscopicity stability for moisture-sensitive drugs); no negative effects on the disintegration and dissolution of tablets; and the fact that often LubriTose SD performed slightly better than its corresponding physical mixture.
0 4
6
8
10
12
Compression(kN)
Figure 6 - Ejection force curve of ibuprofen tablets at 25rpm. Table IV - The stability results of aspirin tablets. 0 day
LT PM
A+1.80S
100.4 101.2
1.2
Ibuprofen + physical mixture
0
Content (%) Piroxicam LT Piroxicam PM
1.4
60 °C, 10 days
RH 92.5 %, 10 days
Cont. (%)
RS (%)
Cont. (%)
RS (%)
Cont. (%)
RS (%)
100.0 100.0
0.14 0.19
100.2 101.6
0.07 0.36
103.4 97.2
0.20 0.45
In accordance with the provisions of China Pharmacopoeia, the related substances of aspirin should not exceed 0.3 %. RS = related substances.
mixture on improving the hygroscopic drugs stability, which may contribute to the very low moisture absorption of LubriTose SD. 2.5. Effects on low dose drugs content uniformity The tablets’ content uniformity of three drugs is shown in Table V. According to Chinese Pharmacopoeia, when A + 1.8S < 15, it notes the qualified uniformity, among which, S is standard deviation of content, and A is the absolute value of the difference between 100 and average content. Both groups were qualified. It was argued that LubriTose SD had no negative effects on the content uniformity of low dose drugs, and even performed better than the physical mixture. Similarly with spray-dried lactose, LubriTose SD had perfect flowability, which can be seen from the low angle of repose and high flow velocity. Good flowability would reduce tablet weight variation and improve content uniformity. In addition, LubriTose SD had a very narrow size distribution, from 60 to 150 μm. The size of the model drugs after 100-mesh sieving Table VI - The dissolution results of model drugs (n = 6).
Average disolution (%) LT PM
Mefenamic acid
Piroxicam
Simvastatin
Ibuprofen
Puerarin
Breviscapine
93.49 ± 0.95 91.45 ± 1.25
96.22 ± 0.99 93.2 ± 0.93
96.87 ± 1.23 102.31 ± 0.76
92.96 ± 1.75 91.10 ± 0.89
95.46 ± 0.68 93.76 ± 1.43
61.37 ± 2.87 62.86 ± 3.15
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Comparative evaluation of a co-processed self-lubricating excipient LubriTose SD as a direct compression vehicle J.-L. Tian, C. Tian, X. Ke
J. DRUG DEL. SCI. TECH., 22 (6) 562-567 2012
In summary, it was demonstrated that using of GMS in a DC tableting could fulfill the lubricant role successfully. LubriTose SD is a co-processed material with self-lubricating properties; it is promisingly suitable for oral solid formulation of hydrophobic drugs, such as powder direct compression.
9. 10.
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Manuscript Received 14 May 2012, accepted for publication 20 July 2012.
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