#### HECKEL AND KAWAKITA ANALYSES OF GRANULES OF THE CRUDE LEAVES EXTRACT OF VERNONIA GALAMENSIS PREPARED USING GELATIN AS BINDER

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**HECKEL AND KAWAKITA ANALYSES OF GRANULES OF THE CRUDE LEAVES EXTRACT OF VERNONIA GALAMENSIS PREPARED USING GELATIN AS BINDER**

M. Autamashih*^{1}, A. B. Isah^{1}, T. S. Allagh ^{1} and M. A. Ibrahim ^{2}

Department of Pharmaceutics and Pharmaceutical Microbiology, Faculty of Pharmaceutical Sciences, Ahmadu Bello University ^{1}, Zaria, Nigeria

Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, University of Jos ^{2}, Nigeria

**ABSTRACT**

The powdered leaf of *Vernonia galamensis* (Asteraceae) is a herbal drug used in the treatment of diabetes mellitus in folk medicine in northern Nigeria. The crude aqueous extract of the leaves is deliquescent and usually stored in airtight desiccators. Efforts to use common diluents such as lactose, starch, and magnesium carbonate for tablet formulation of the extract produced tablets with defects such as “sticking” and “picking”. The purpose of this study was to use the Heckel and Kawakita equations to investigate the compressibility of the granules of the deliquescent crude extract of *Vernonia galamensis* prepared using gelatin a universally accepted pharmaceutical binder and selected efflorescent pharmaceutical diluents namely; Aerosil^{®} 200, Avicel^{®} PH 103 and calcium phosphate. The Kawakita model provided an excellent fit having higher R^{2} values than the Heckel model. The very low P_{K} values of the Kawakita (indicating good fluidity) for all the different formulations made it preferable in explaining the compressibility of granules of the extract. The ranking for good compressibility based on the diluent type using gelatin as binder was as follows; calcium phosphate > aerosil^{®} 200 > Avicel^{®} PH 103.

Keywords:Compressibility,
Heckel equation, Kawakita equation, Gelatin, |

Diluents

**INTRODUCTION: **In folk medicine, herbal drugs are usually prepared in form o extracts and solution by maceration, extraction and decoction techniques^{ 1}. Oral communication with traditional herbalists in northern Nigeria revealed the decoction of leaves of *Vernonia galamensis* (Asteraceae) have been used in folk medicine for ages in the treatment of diabetes mellitus. The dry powdered leaves of *Vernonia galamensis* (Asteraceae) have been used by traditional herbalists in northern Nigeria for ages in the treatment of diabetes mellitus. Folkloric medicines however, have neither standard dose nor acceptable method of formulation ^{1}.

This necessitates the need for standardization and formulation of the medicines in conformity with current Good Manufacturing Practice (GMP). Some researchers have chosen the tablet over other dosage forms for the formulation of medicinal plant extracts ^{2} due to the advantages of the former. Most plant extracts are hygroscopic and susceptibility to microbial degradation, so the choice of a suitable pharmaceutical dosage form that will conform to current GMP cannot be overemphasized. Tablets are by far the most frequently used dosage form for all active medicinal ingredients; they have advantages for both manufacturer and user.

Ease of administration, convenience of administration, and accurate dosing make tablets a versatile and popular dosage form ^{3}.

The purpose of this study was to use the Heckel and Kawakita equations to investigate the consolidation behavior of granules of the dry crude leaf extract of *Vernonia galamensis *(EVG) prepared using gelatin (GLT) a universally accepted pharmaceutical binder and selected efflorescent pharmaceutical diluents namely; Aerosil^{®} 200 (AR), Avicel^{®} PH 101 (AV) and calcium phosphate (CP). The EVG is highly hydroscopic and deliquescent and is stored over silica gel in a dessicator. Efforts to use common diluents such as lactose, starch, and magnesium carbonate for tablet formulation of the extract produced tablets with defects such as “sticking” and “picking”. In the attempt to check the deliquescent characteristics of the extract, efflorescent diluents were selected for this formulation process.

The Heckel equation has by far been the most popular in recent years among pharmaceutical scientists, and many apparent yield pressure values (‘in-die”, P_{y}) and mean yield pressure values (‘out-of-die’) of active substances and tableting excipients have been published ^{4}. The model has often been applied to study powder mixtures and to evaluate granule manufacture. Of recent, scientists have also made attempts to use the Heckel relation for predicting powder characteristics of active crude plant extracts ^{2}.

Despite the versatility of the Heckel equation however, drawbacks and limitations to its use have been reported^{ 4}. Some scientists have used more than one equation to try to eliminate the shortcomings of the other^{ 5, 6}. Hence, in this study, both Heckel and Kawakita plots have been used to assess the compression characteristics of EVG in combination with the three efflorescent diluents; AR, CP and AV.

**Heckel Analysis:** The plots constructed according to the Heckel equation ^{7} were used to characterize the consolidation behavior of the formulations:

Ln [1/(1–*D*)] = *KP *+*A ……………………………………………… *(1)

Where *D *is the ratio of the density of the powder mass at pressure *P *to the density of the powder mixture (*i.e., *relative density); *K*, the slope of the straight portion of the graph, reflects the reduction in porosity or the resistance to volume reduction of granules and *A *is a constant. The yield pressure, *PY, *is usually calculated as the reciprocal of the linear portion of the slope of the Heckel plot. The relative density *D _{A} *was calculated from the intercept,

*A*, using the equation:

*D _{A} *= 1–e

^{–A}……………………………………..……………………… (2)

*D _{B}*, the relative density during the rearrangement phase was calculated from the difference between

*D*and

_{A}*D*(relative density of the granules at nil pressure).

_{O}**Kawakita Analysis:** The Kawakita equation ^{8} describes the relationship between the volume reduction of powder column and the applied pressure;

C = [V_{o} – V/ V_{o}] = [abP/1 + bP]…………………………………(4)

Where, C, is degree of volume reduction, *V _{o}* is Initial volume, V is volume of powder column under the applied pressure P. a, b are constants characteristic to powder being compressed. The equation above can be re arranged in linear form as:

P/C = P/a + 1/ab ………………………………………………….. (5)

From the graphical presentation of P/C versus P, the constants maybe evaluated. The constant “a”, is given as a reciprocal of the slope from the linear portion of the plot and equivalent to the value of C at infinitely high pressures. 1/ab is the intercept. a, gives an indication of the maximum volume reduction available and is considered to describe the compressibility of a powder, while b is considered to describe an inclination toward volume reduction. However, the actual physical meaning of the constants a and b have been in question^{ 9}. Consequently, Kawakita in 1983 have applied another equation in describing the volume reduction on tapping and vibrating processes, where the pressure P, is replaced by the tapping number, N^{ 10}.

N/C = [(1/a) N ¸ 1/ab] …………………………………………… (6)

Where, N is the tapping number, C is the degree of volume reduction and a and b are constants. C in equation vi is given by;

C = [V_{o} – V_{N}] ¸ V_{o } …………………..……………………………… (7)

Where V_{o} is the initial apparent volume and V_{N}, the volume at tapping number N. The constants of Kawakita equation can be used to estimate the flow and cohesiveness properties of powders. Constant “a”, describes the compressibility and constant “1/b” describes cohesive properties of powders or the fastness of how the final packing stage is achieved ^{9}.

**MATERIALS AND METHODS:**

**Materials:** These include Gelatin (May and Baker, Germany), aerosil^{®} 200 (GmbH, Meggle, Germany), avicel PH-103 (FMC Corporation, USA) calcium phosphate (BDH chemicals Ltd., Poole, England), maize starch (May and Baker, Germany) and the leaves of *Vernonia galamensis* (collected from the natural habitat of Ahmadu Bello University, Zaria, Nigeria and identified in the herbarium unit of the Department of Biological Sciences of the University where a sample was deposited with a voucher specimen number 994).

**Methods:**

**Preparation of the extract:**Leaves of*Vernonia galamensis*were plugged from the main stem in June, 2010 and washed, air dried, milled to a coarse powder (particle size ≤ 1000 um) and macerated in distilled water for 24 h at room temperature and the liquid extract filtered through a calico cloth and concentrated to a ratio of 5:1 using a rotary evaporator. The concentrated filtrate was then transferred into a tray and dried in an oven at 40 °C, pulverized using a mortar and pestle and then passed through a 150 µm sieve.**Preparation of granules:**The wet granulation, a versatile process, was employed because of the very high humidity and poor flow property of the extract^{11}. Appropriate quantities of the dry extract and diluent ratio 1:1.4 were mixed in a mortar for 5 minutes. Disintegrant (maize starch, 6.8% w/w) was added and mixing continued for another 5 minutes. The liquid binder prepared using gelatin 5% w/v in water was added in 1-mL portions and mixed with a pestle. The moistened mass was forced through a 1000µm sieve, dried at 40 °C for 2 h to give a moisture content of 4% – 6%, determined on an Ultra X moisture balance (August Gronert Co., Germany). The granules were again passed through a 1000 µm screen to break up agglomerates.

**Granule Analysis:**

**Moisture content analysis:**One gram (1.0g) of the sample was transferred into each of several Petri dishes and then dried in an oven at 105°C until a constant weight was obtained. The moisture content was then determined as the ratio of weight of moisture loss to weight of sample expressed as a percentage.**Angle of repose:**The static angle of repose, a, was measured according to the fixed funnel and free standing cone method. A funnel was clamped with its tip 2cm above a graph paper placed on a flat horizontal surface. The powders were carefully poured through the funnel until the apex of the cone thus formed just reached the tip of the funnel. The mean diameters of the base of the powder cones were determined and the tangent of the angle of repose calculated using the equation:

Tan a = 2h/D …………………………………………………………. (1)

**Bulk density, Tapped density, Hausner’s ratio and Carr’s index of compressibility:**Thirty gram (30 g) quantity each of the granules was carefully poured through a short stem glass funnel in a 100ml measuring cylinder and the volume, V_{0}, occupied by the granules without tapping was noted. After 100 taps on the table, the occupied volume V_{ 100}was read. The bulk and tap densities were calculated as the ratio of weight to volume (V_{ 0}and V_{ 100}respectively). Carr’s index and Hausner’s ratio were calculated using the following equations:-

Carr’s index= Tapped density – Bulk density x 100 … (2)

Tapped density

Hausner’s ratio = Tapped density ……………………… (3)

Bulk density

**Preparation of compacts:**The tablet formula was designed by varying the type and quantities of the excipients to obtain tablets of highest quality (**Table 1**). Tablets equivalent to 300mg of granules were produced by compressing the granules for 60 s at 25 KN (303 MNm^{-2}) using a single punch tablet machine (Tianxiang and Chentai Pharmaceutical Machinery Co Ltd, Shanghai, China) fitted with 10.5 mm flat punch and die set. After ejection, the tablets were stored over silica gel in a dessicator for 24 h to allow for elastic recovery and hardening.

**TABLE 1: MEAN GRANULE SIZE AND HECKEL CONSTANTS FOR DIFFERENT FORMULATIONS**

Diluent |
Binder (GLT) (%) |
Py (MNm-2) |
A |
D_{A} |
D_{o} |
D_{B} |
R^{2} |

AR | 5.0 | 711.24±1.70 | -0.18±0.01 | -0.19 | 0.18±0.07 | -0.37 | 0.995 |

AV | 5.0 | 323.21±2.40 | -0.69±0.01 | -0.99 | 0.15±0.04 | -1.14 | 0.999 |

CP | 5.0 | 115.94±2.10 | -2.19±0.02 | -7.95 | 0.30±0.01 | -8.25 | 0.999 |

GLT = Gelatin, AR = Aerosil^{®} 200, AV = Avicel^{®} PH 101 and CP = calcium phosphate. Results were expressed as mean ± SD of three runs

**Data analysis: **The graphs were plotted and data analyzed using GraphPad Prism^{®} version 5.03 software. The data used to plot the graphs were the mean of three readings ± SD, granule size, moisture content

**RESULTS AND DISCUSSIONS: **Three types of powder compression behavior have been identified based on the Heckel’s equation, namely type A, B and C ^{12}. **Figure 1** depicts the Heckel plots obtained for the granulations formulated with AR, AV and CP as diluents and GLT at 5% w/v concentration as binder. The plots especially for formulations containing AR and AV exhibited linear and near parallel relationships at all applied pressures, where increase compression pressure significantly increase the relative density of the compacts. This implies that the plots are indicative of type-A materials and that all the granules principally undergo deformation by plastic flow ^{13}.

**FIG. 1: HECKEL PLOTS FOR EVG COMPACTS PRODUCED USING SELECTED DILUENTS AND GLT (5%W/V) AS BINDER **

Points refer to mean ± SD values (*n* = 3)

The observed deformation characteristics (plastic flow) for all samples used may be due to the extreme hygroscopic and deliquescent nature of the extract. This is because earlier report had indicated that the deformation characteristics for all samples of the extremely hygroscopic and deliquescent chondroitin sulfate were by plastic flow ^{14}. The increase in slope at higher pressure indicates an increase in the rate of densification as the void spaces between particles decrease. Figure 1 also shows that the EVG/AV compacts were compressed at higher relative densities than those of EVG/AR and EVG/CP.

The tendency of the material to deform either by plastic flow or fragmentation is described by the yield pressure *P _{y}*, which is an important indication of granule compressibility. A faster degree of plastic deformation is reflected by a low

*P*value (steep slope) in a general sense. Table 1 show that formulations made with AV as diluent gave lower

_{y }*P*values than those with either AR or CP, indicating that granules of the former deformed plastically at lower pressures than those of the later ones. But negative intercepts were observed in all the different formulations using the selected efflorescent diluents. This negative values of intercepts may be due to the intrinsic characteristics of the extract; being deliquescent in nature. The negative intercepts gave rise to negative values of both

_{y}*D*and

_{A}*D*by calculation.

_{B}Given some more thoughts to this; *D _{A}* represents the total degree of densification at zero and low pressures and

*D*represents the particle rearrangement phase in the early compression stages which also indicate the extent of granule fragmentation

_{B }^{9}. This means that for any situation where zero values of

*D*and

_{A}*D*obtained, it would mean that there is no densification at zero and low pressure and no particle rearrangement phase or granule fragmentation at all. But in this situation where negative values (less than zero values) of the

_{B }are*D*and

_{A}*D*were obtained, it is impracticable to explain the degree of densification at zero and low pressures and the particle rearrangement phase or the extent of granule fragmentation by the use of the Heckel equation. This is a limitation of the equation in this study.

_{B }**Figure 2** shows the kawakita plots for *Vernonia galamensis* tablet formulations containing selected diluents and GLT as binder, where a linear relationship between N/C and N is obtained at all compression pressures used with correlation coefficient ≥ 0.99 for all the formulations, and hence, the equation can be used to predict the densification mechanisms of the *Vernonia galamensis* formulations better than the Heckel equation where negative intercepts were observed.

**FIG. 2: KAWAKITA PLOTS FOR EVG COMPACTS PRODUCED USING SELECTED DILUENTS AND GLT (5%W/V) USED AS BINDER**

Points refer to mean ± SD values (*n* = 3)

Values of 1/b and 1/ab were obtained from the slope and intercept of the plots respectively. The tapping experiments were performed on all samples and a and 1/b were evaluated. It was observed from **Table 2** (which shows the Kawakita constants) that values of ‘a’ were smaller in the formulations with CP than in the formulation with AR and AV implying that the fluidity of the CP is better.

**TABLE 2: KAWAKITA CONSTANTS FOR DIFFERENT FORMULATIONS OF VERNONIA GALAMENSIS USING GELATIN (5%W/V) AS BINDER**

Diluent type |
1/a |
a |
Di(1-a) |
1/ab |
P_{k}(1/b) |
R^{2} |

AR |
3.940±0.1 | 0.254 | 0.746 | 17.12±0.1 | 4.345 | 0.996 |

AV |
4.635±0.1 | 0.216 | 0.784 | 21.13±0.1 | 4.559 | 0.990 |

CP |
4.090±0.1 | 0.244 | 0.756 | 20.65±0.1 | 5.049 | 0.998 |

AR = Aerosil^{®} 200, AV = Avicel^{®} PH 101 and CP = calcium phosphate. Results were expressed as mean ± SD of three runs

Previous study have indicated that the smaller the values of ‘a’, the better the fluidity ^{9}. The value of P_{K} for formulations with AR is highest implying that the cohesiveness of the granules would be higher than others. The low value of P_{K} in other formulations is indicative of the reduction in cohesion. A low value of P_{K} is indicative of materials that are soft and that readily deform plastically under pressure ^{9}.

**CONCLUSION: **Two models namely; Heckel and Kawakita models were fitted to the pressure-density-volume data. Although the Heckel model presented acceptably high R^{2} values, the negative values of D_{A} and D_{B} made it difficult to practically explain the degree of densification at zero and low pressures and the particle rearrangement phase and extent of granule fragmentation. We can therefore conclude that the Kawakita model with high R^{2} values and no negative intercept is preferred in explaining the compressional characteristics of granules of *Vernonia galamensis* prepared using GLT as binder along with the selected diluents (AR, AV, CP).

**ACKNOWLEDGEMENTS: **The authors are grateful to Abu Garba, Lido Gilama and Sunday Dzarma of the National Institute for Pharmaceutical Research and Development for technical assistance in the laboratories.

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# Article Information

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2566-2571

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English

Ijpsr

M. Autamashih*, A. B. Isah, T. S. Allagh and M. A. Ibrahim

Department of Pharmaceutics and Pharmaceutical Microbiology, Faculty of Pharmaceutical Sciences, Ahmadu Bello University, Zaria, Nigeria

27 April, 2011

25 September, 2011

29 September, 2011

http://dx.doi.org/10.13040/IJPSR.0975-8232.2(10).2566-71

01 October, 2011