Enhancement of Drug Dissolution of Erlotinib Tablets by Micronization Technique Using Pharmaceutical Experimental Design

Lung cancer is the second most frequent cancer and among the top cause of death worldwide. Chemotherapy is the main therapeutic option for non-small-cell lung cancer (NSCLC), which accounts for the majority of all lung malignancies. The aim of the current work was to develop a tablet formulation having increased drug release profile to improve the bioavailability in order to reduce the dose of the drug. In this present study, Erlotinib tablet was prepared using micronization technique which showed increase drug release profile. Film-coated tablets containing Erlotinib hydrochloride (150 mg) were prepared by dry granulation technique and coated using Opadry ready-mix. Tablets were characterized for Hardness, Friability, Potency and Drug release profile. Drug release was checked in 0.1 N HCL containing 0.5 % SLS and biorelevant dissolution media up to 60 minutes. Tablets of the selected batch were subjected to dissolution in biorelevant media and compare with reference product. The improvement in the drug release was observed in the biorelevant media in comparison with reference product. The in-vitrodissolution data demonstrated the potential of micronization technology to prepare tablets with improved bioavailability of the drug. Original Research Article Kumar et al.; JPRI, 33(51A): 70-78, 2021; Article no.JPRI.77409 71


INTRODUCTION
Lung cancer is the most frequent cancer and the leading cause of cancer fatalities. Chemotherapy is the primary therapeutic option for non-smallcell lung cancer (NSCLC), which accounts for the majority of lung cancers [1][2].
Erlotinib is an anticancer medicine that inhibits the tyrosine kinase of the epidermal growth factor receptor (EGFR). It is used to treat non-small cell lung cancer (NSCLC) and pancreatic cancer. Erlotinib's solubility is pH dependent, having a low solubility at neutral pH and a higher solubility at pH less than 5. It is classified as a class II drug by the Biopharmaceutical Classification System (BCS), which means it has a low solubility and a high permeability. It is absorbed in the GI tract and reaches its maximal concentration in the blood after 1.4 hours. Erlotinib has a daily dose of 150 mg for NSCLC. In healthy subjects, absolute bioavailability (BA) was found to be only59 percent [3][4][5].
Erlotinib suppresses signaling pathways such as cell proliferation, metastasis, and angiogenesis. Folliculitis, diarrhoea, dry skin, and lethargy are all common adverse effects of EGFR TKIs. However, some adverse effects may worsen, and new symptoms may appear after months or years of medication. This could lead to dose reductions or even the premature discontinuation of effective treatment. Long-term side effects in individuals treated with erlotinib for lung adenocarcinoma with an EGFR activating mutation. Due to the good tumour response to this EGFR TKI, patients and their treating physicians were highly motivated to continue treatment. As a result, early and ongoing side effects like folliculitis and diarrhoea were deemed tolerable. Skin toxicity remained in all cases. Many patients may receive reduce dose because of these side effects [6][7][8][9].
The size of drug particles affects their oral bioavailability because smaller particles have more surface area, which increases their dissolution. The solubility of the active pharmaceutical ingredient is proportional to the size of the drug particle. As the particle size decreases, the surface area to volume ratio increases. Because of the larger surface area, there is greater interaction with the solvent, which results in a higher solubility. Particle size reduction is a cost-effective, reproducible, and commercially feasible approach for increasing solubility. Micronization is a conventional technique for the particle size reduction. Micronization enhances the rate of drug dissolution by increasing the surface area of the drug, but it does not increase equilibrium solubility. The rate of dissolution of these pharmaceuticals is improved by reducing the particle size of these drugs, which results in an increase in surface area. Milling techniques employing a jet mill are used to micronize pharmaceuticals. The micronization techniques are applied to various poorly soluble drugs for improving their absorption, and as a result to increase their bioavailability [10][11][12].
For the drug products meant for oral administration, particle size of drugs and components are very important and can affect the manufacturing processing, solubility and invivo bioavailability. Numerous drugs that have been developed for pharmaceutical administration purpose have low aqueous solubility and are categorized in class II and IV of the biopharmaceutical classification system. One of the limiting parameters for achieving excellent bioavailability is the dissolution rate. Particle size reduction, which increases surface area, is a promising strategy for improving dissolution rate and, as a result, bioavailability of poorly watersoluble medicines can be improved [12][13]. The aim of the study was to use micronization techniques to reduce particle size and accelerate the rate of Erlotinib dissolution from the tablet dosage form. Tablet formulation prepared by cosifting of functional excipients and micronized erlotinib hydrochloride was analysed for drug dissolution in bio-relevant media and compared with available reference drug.

Formulation of Tablets
The milling of drug substance was done by using Air Jet Mill (Promas Engineering, Mumbai).
Milling performed at air pressure 3-4 kg/cm 2 .The particle size of milled material was checked with laser diffraction technique ( Table 1). The tablets were manufactured using dry granulation technique.

Optimization of the Tablet Formulation
Statistically designed experiments (Table 3)

Tablet Characterization
 Flow property of Granules: The bulk density, tap density, and Hausner ratio of the granules were all measured using following equation [14][15].
The compressibility index and Hausner ratio are calculated using measured values for bulk density (ρ bulk) and tapped density (ρ tapped) as follows: Compressibility Index = 100 x [ρ tapped -ρ bulk ] /ρ tapped (1)  Weight Variation: The test for weight uniformity was carried out by weighing 20 tablets at random using weighing balance (Mettler Toledo, AG 204) and noting the average weight and standard deviation was determined [16][17].  Thickness: The micrometer caliper was used to measure the thickness of ten preweighed tablets from each batch, and the average thickness and standard deviation was determined [16][17].  Friability: The USP 35 monograph on tablet friability was used to determine tablet friability. Twenty tablets (W1) were weighed and placed in a friabilator, which was rotated at 25 rpm for four minutes. After removing the fines (W2), the tablets were reweighed and the friability was evaluated using the formula below.

RESULTS AND DISCUSSION
A total of five formulations (Table 4) of erlotinib tablets with different ratio of disintegrant and surfactant levels were prepared using factorial design using two factorsconcentration of SLS (X1), the concentration of SSG (X2) at two levels.
The results demonstrated that batch with mid value of SLS concentration and SSG concentration showed good dissolution characteristics and disintegration time. The extent of in vitro drug release was determined by performing multiple linear regression analysis using Design Expert Software version 13.0.5.0. The 3D response surface plot (Fig. 1) and contour plot (Fig. 2) were developed to study the effects of variables on the disintegration of the drug graphically.
The tablet's were formulated using Erlotinib Hydrochloride as active pharmaceutical agent, Lactose monohydrate and Microcrystalline Cellulose as fillers, Sodium Lauryl Sulphate as surfactant, Sodium Starch Glycolate (SSG) as disintegrant and Magnesium stearate was added to enhance the powder flow. As a result, there was a consistent flow from the hopper to the die. It facilitates the ejection of tablets from the die cavity by reducing inter-particle friction, by preventing tablet material from adhering to machine components such as punches and dies.Excipients were sieved through #40. The cosifting and mixing of dry excipients with erlotinib hydrochloride was done twice to ensure proper mixing of functional excipients with drug substance. Dry mix powder was subjected to prepare flakes. Flakes were than broken in to granules with using 1.5 mm screen and milled granules mixed with extra granular disintegrant in blender for further lubrication was done using magnesium stearate. The granules were characterize for the flow property (Table 5), which have shown passable flow characteristics. The particle size of granules has been shown in Table 6 and Fig. 3, respectively.

Tablet Characteristics
The mix was compressed using 10.3 mm Round punches on a 12-station single rotary compression machine (Rimek Mini Press, Ahmedabad, India). All the tablets were characterize for weight variation test, hardness, thickness, disintegration and dissolution test. All of the formulations disintegrated quickly and were well within official limits. By introducing discs into 900ml purified water at 37±2ºC in water, the disintegration time of six tablets was measured. It shows that the drug is fully available for dissolution and absorption from the GIT.

Dissolution Study
The optimised batch was selected for the in-vitro drug release study using USP Dissolution Apparatus II.

CONCLUSION
The granules made using micronized API exhibited flow properties suitable to carry out compression. The in-vitrodissolution results revealed that biorelevent media is reflecting discriminating behaviour for the same formulation. The outcome of this study clearly indicates that a stable oral tablets of erlotinib can be developed using varying concentration of SSG and SLS, resulting in improved dissolution characteristics. This outcome of the study indicates the application of micronization technique in enhanced dissolution, which may further leads to increased oral bioavailability. Furthermore, in-vivo studies could give a better understanding of the results observed in present investigation and targeted applications of tablets.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT AND ETHICAL APPROVAL
It is not applicable.