Formulation And Optimization of Low Dose Potent Drug by Using Rapid Mixing Technology Based on Qbd

2.1 Endometriosis:

Endometriosis is a chronic, estrogen-dependent gynecological disorder characterized by the presence of endometrial-like tissue outside the uterine cavity. It is one of the most prevalent reproductive disorders affecting women of reproductive age and is associated with chronic pelvic pain, dysmenorrhea, dyspareunia, infertility, and reduced quality of life. Globally, endometriosis affects approximately 10% of women of reproductive age and up to 50% of women experiencing infertility. The disease imposes a substantial socioeconomic burden due to healthcare expenditures, loss of productivity, and long-term management requirements. Despite advances in diagnostic and therapeutic approaches, delayed diagnosis and inadequate treatment remain major clinical challenges.

Hormonal therapy is considered the cornerstone of endometriosis management because the disease is highly dependent on estrogen stimulation. Various hormonal agents, including progestins, combined oral contraceptives, gonadotropin-releasing hormone (GnRH) agonists, and aromatase inhibitors, have demonstrated effectiveness in reducing pain symptoms and suppressing the progression of endometriotic lesions. Among these therapies, progestin-based formulations are widely prescribed due to their favorable efficacy and safety profile. Hormonal tablets provide a convenient and non-invasive route of administration, ensuring patient compliance and long-term therapeutic benefits. However, the development of high-quality hormonal tablet formulations remains challenging because of the low-dose nature of hormonal drugs, stringent content uniformity requirements, and the need for robust manufacturing processes.

2.2 Tablet Dosage forms in Hormonal Drug Delevery

Tablets continue to be the most widely used pharmaceutical dosage form because of their stability, convenience, accurate dosing, ease of administration, and cost-effective manufacturing. The successful development of tablet formulations depends on the appropriate selection of excipients and manufacturing processes capable of producing tablets with acceptable physical and performance characteristics. Critical quality attributes such as hardness, friability, content uniformity, dissolution, and stability significantly influence the therapeutic effectiveness of tablet products. Therefore, optimization of formulation variables and process parameters is essential to ensure consistent product quality.

Granulation is a critical step in tablet manufacturing and plays a significant role in determining the flowability, compressibility, and uniformity of powder blends. Among the available manufacturing approaches, wet granulation is extensively employed for pharmaceutical formulations due to its ability to improve powder handling characteristics and enhance content uniformity. Wet granulation involves the aggregation of powder particles using a granulating liquid, resulting in granules with improved mechanical strength and compressibility. The process generally consists of wetting and nucleation, granule growth and consolidation, followed by drying and sizing operations. Compared with direct compression, wet granulation provides better control over blend uniformity and tablet quality, particularly for formulations containing low-dose active pharmaceutical ingredients.

Several process variables influence the quality of granules and final tablets produced by wet granulation. Parameters such as binder concentration, granulation time, impeller speed, drying conditions, and excipient composition can significantly affect granule size distribution, flow properties, tablet hardness, and dissolution behavior. Consequently, systematic optimization of these variables is required to develop a robust manufacturing process capable of consistently producing products that meet predefined quality specifications.

2.3 Quality by Design Approach

In recent years, the pharmaceutical industry has shifted from traditional quality-by-testing approaches toward Quality by Design (QbD), a science- and risk-based framework for pharmaceutical development. The concept of QbD was introduced by regulatory authorities, including the United States Food and Drug Administration (FDA) and the International Council for Harmonisation (ICH), to enhance product quality through systematic process understanding and control. According to ICH Q8(R2), QbD is defined as a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding based on sound scientific principles and quality risk management.

2.3.1 Quality Target Product Profile (QTPP)

The QbD framework involves the identification of a Quality Target Product Profile (QTPP), determination of Critical Quality Attributes (CQAs), risk assessment of material attributes and process parameters, establishment of a design space, and implementation of an effective control strategy.

2.3.2 Critical Quality Attributes (CQAs)

This approach enables manufacturers to identify sources of variability and establish scientifically justified operating ranges for critical process parameters. By integrating product knowledge with process understanding, QbD facilitates continuous improvement, regulatory flexibility, and enhanced product quality throughout the product lifecycle.

2.3.3 Quality Risk Management

Risk assessment tools such as Failure Mode and Effects Analysis (FMEA) are commonly employed within the QbD framework to identify and prioritize factors that may affect product quality. Through systematic evaluation of severity, occurrence, and detectability of potential failures, critical formulation and process variables can be identified and controlled. The information generated through risk assessment provides the foundation for subsequent experimental studies and optimization efforts.

2.3.4 Design of Experiments (DOE)

Design of Experiments (DOE) is a powerful statistical methodology widely used in QbD-based pharmaceutical development. DOE enables the systematic evaluation of multiple variables simultaneously while identifying their individual and interaction effects on product responses. Compared with conventional one-factor-at-a-time approaches, DOE reduces experimental workload, improves process understanding, and facilitates efficient optimization. Factorial designs, response surface methodologies, and other statistical experimental designs have become essential tools for identifying significant factors affecting pharmaceutical formulations and manufacturing processes.

2.3.5 Factorial Design Methodology

Among DOE techniques, factorial design is particularly useful during the screening and optimization stages of formulation development. It enables the evaluation of critical formulation and process parameters while establishing mathematical relationships between independent variables and response variables. The generated models provide valuable insights into process behavior and support the development of robust formulations with improved performance characteristics.

Considering the increasing demand for affordable and high-quality hormonal therapies, there is a need to develop optimized hormonal tablet formulations using scientifically driven approaches. Application of QbD principles in combination with DOE provides a systematic strategy for understanding formulation variables, identifying critical process parameters, and achieving consistent product quality. Such an approach ensures compliance with regulatory expectations while minimizing development time and manufacturing variability.

2.3.6 Optimization of Formulation and Process Variables

Therefore, the present study focuses on the development and optimization of a hormonal tablet formulation employing wet granulation technology under a Quality by Design framework. Risk assessment and Design of Experiments were utilized to identify and optimize critical formulation and process variables influencing tablet quality attributes. The ultimate objective was to establish a robust and reproducible manufacturing process capable of producing a cost-effective hormonal tablet formulation that meets predefined quality requirements and regulatory standards.

3.0 MATERIALS AND METHOD

3.1Materials

The active pharmaceutical ingredient (API), a low-dose potent hormonal drug (2 mg strength), was obtained from Chemo. The excipients used in the formulation included microcrystalline cellulose (MCC PH 102) and lactose monohydrate as diluents, crospovidone as a disintegrant, povidone K-25 as a binder, talc as a glidant, magnesium stearate as a lubricant, and sodium lauryl sulfate as a surfactant. All chemicals and reagents used in the study were of analytical grade.

3.2 Preformulation Studies

The API was initially characterized for its physical appearance, solubility, moisture content, and UV spectral properties. UV spectral analysis was performed by dissolving the drug in acetonitrile and scanning the solution in the wavelength range of 200–400 nm to determine the absorption maximum (λmax). Moisture content was evaluated by the loss-on-drying method at 105°C. Solubility studies were conducted in different media, and the drug concentration was quantified using a validated HPLC method.

Flow properties of the drug substance were evaluated by determining the angle of repose, bulk density, tapped density, Carr’s compressibility index, and Hausner’s ratio. Drug–excipient compatibility studies were performed by storing binary mixtures of API and excipients under accelerated stability conditions (40 ± 2°C/75 ± 5% RH) for 30 days. Samples were analyzed for physical appearance, assay, and related substances to assess compatibility.

3.3 Quality by Design (QbD) Approach

A Quality by Design (QbD) framework was adopted to systematically develop the formulation. The Quality Target Product Profile (QTPP) was established based on the intended product characteristics, including dosage form, strength, dissolution, content uniformity, and stability requirements. Critical Quality Attributes (CQAs), Critical Material Attributes (CMAs), and Critical Process Parameters (CPPs) were identified through risk assessment studies.

Risk assessment was performed to evaluate the potential impact of material attributes and process variables on product quality. Parameters such as particle size distribution, flow properties, blending time, lubrication time, and compression force were assessed for their influence on content uniformity, assay, dissolution, and related substances.

3.4 Formulation Development

Multiple trial formulations were prepared using wet granulation technology. The composition consisted of API, MCC PH 102, lactose monohydrate, crospovidone, povidone K-25, talc, and magnesium stearate. The final tablet weight was maintained at 140 mg

3.5 Rapid Mixing and Granulation

Rapid Mixing Technology was employed using a Rapid Mixer Granulator (RMG). The API and excipients were accurately weighed and sifted through appropriate sieves before blending. The dry ingredients were mixed in the RMG to achieve uniform distribution of the low-dose API.

A binder solution was prepared by dissolving povidone K-25 in isopropyl alcohol. The binder solution was gradually added to the powder blend during granulation. The wet mass was kneaded to obtain uniform granules and subsequently dried in a fluidized bed dryer until the desired moisture level was achieved.

The dried granules were sized and blended with extragranular crospovidone. Talc and magnesium stearate were added during the lubrication stage and mixed for a specified duration to obtain the final blend.

3.6 Tablet Compression

The lubricated blend was compressed into tablets using a rotary tablet compression machine. Compression parameters were optimized to achieve the desired hardness, thickness, weight uniformity, and mechanical strength.

3.7 Evaluation of Tablets

The prepared tablets were evaluated for critical quality attributes including appearance, weight variation, thickness, hardness, friability, disintegration time, assay, content uniformity, dissolution, and related substances.

Hardness was measured using a tablet hardness tester, while friability was determined using a friabilator operated for 100 revolutions. Weight variation was assessed by individually weighing twenty tablets. Disintegration testing was carried out using a USP disintegration apparatus maintained at 37 ± 2°C.

Drug content and assay were determined using a validated HPLC method employing a C18 column, with UV detection at 308 nm. Dissolution studies were performed in different dissolution media, including 0.1 N hydrochloric acid, acetate buffer (pH 4.5), and phosphate buffer (pH 6.8), using a USP dissolution apparatus.

3.8 Stability Studies

The optimized formulation was subjected to accelerated stability testing under ICH conditions of 40 ± 2°C and 75 ± 5% relative humidity. Samples were evaluated periodically for appearance, assay, dissolution, water content, and related substances. The stability data were compared with initial values to confirm the robustness and stability of the developed formulation.

4.0 RESULT AND DISCUSSION

4.1 Drug Identification and Characterization

Using a UV spectrophotometer to scan the drug's maximum absorbance aids in verifying the reliability of the API. In this process, the wavelength at which the drug exhibits maximum absorbance is identified. Acetonitrile was chosen as the solvent based on its solubility. The spectrum obtained was compared with that of the standard API (308 nm), confirming that the drug exhibits maximum absorbance at 308 nm

 

 

UV Spetrum

 

 

Figure No 1: Effect of various conc. Of Povidone K25 on dissolution

The dissolution study revealed that all formulations successfully met the dissolution requirement of not less than 75% (Q) at 30 minutes. However, excipient variability was closely examined at each interval. It was noted that the optimized formulation (F2) closely matched that of the reference product.

4.10 Related Substances

All impurities remained well below pharmacopeial limits, demonstrating the chemical stability of the formulation.

Table 10. Related Substances of Optimized Formulation

4.11 Stability Studies

Accelerated stability studies demonstrated that the optimized formulation remained stable with no significant changes in assay, dissolution, appearance, or impurity profile.

Table 11. Stability Study Results

4.12 DISCUSSION

The present study successfully demonstrated the application of Rapid Mixing Technology integrated with a Quality by Design approach for the development of a low-dose potent tablet formulation. The optimized formulation (F2) achieved excellent content uniformity, assay, dissolution, and stability characteristics. Risk-based optimization of blending time, lubrication time, compression force, and compression speed significantly improved product quality. The developed formulation showed performance equivalent to the reference product and complied with all predefined quality specifications, confirming the suitability of the proposed manufacturing strategy for low-dose potent drug products.

5.0 ACKNOWLEDGMENT

First and foremost we express our heartfelt sense of gratitude and faithfulness to God’s grace and our family members, which has enabled us to finish our project work successfully.

We express our sincere thanks to our chairman DR. J.K.K. MUNIRAJAH M.Tech (Bolten). Annai JKK Sampoorani Ammal Charitable Trust, for providing all the facilities to carry out this work.

Our sincere gratitude to DR. P. PERUMAL, M.Pharm., Ph.D., FIC., Professor & Principal, JKK Munirajah Institute of Health Sciences College of Pharmacy, T.N.Palayam for his valuable support and encouragement for project work from time to time to complete this work successfully.

With the immense pleasure and pride, we would take opportunity in expressing our deep sense of gratitude to our beloved guide Mr. K.RAJA M.Pharm Professor and  Mr. K.GOBINATH, M.Pharm., Associate Professor,  Department of Pharmaceutics, JKK Munirajah Institute of Health Sciences College of Pharmacy, T.N.Palayam under whose active guidance, innovate ideas, constant inspiration and constant encouragement and personal concern throughout the course of investigation and successful completion of this work.

We express our grateful thanks to all Head of the Department, teaching and non-teaching staffs of JKK Munirajah Institute of Health Sciences College of Pharmacy for their valuable advice and co-operations.

Last but not least, great thanks from the heart to our beloved MOTHER and FATHER. They are our living god, as who guided us in the rightful way to achieve all our activities. They gave the incredible effort to become a successful for bright future in this world. Thanks a lot to our parents.

We express our grateful thanks to Organization of Steril gene life science, Formulation and Development Department, Senior and Junior Scientist for their valuable advice and co-operations.

I whole-heartedly thank my loving friends D.Kumudhavalli, R.Ragu, and Vijayaragavan K  for the help, support, and affection showered on me through their friendship.

This research project would not have been possible without the support of many people and I am thankful to each and every one who are involved in the completion of my project.

REFFERENCES

1. Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, Greb R, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005 Oct 1;20(10):2698-704.
2. Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D'Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertility and sterility. 2009 Jul 1;92(1):68-74.
3. Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco Nardone F, de Cicco Nardone C, et al. Study WE. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertility and sterility. 2011 Aug 1;96(2):366-73.
4. De Graaff AA, D’hooghe TM, Dunselman GA, Dirksen CD, Hummelshoj L. Consortium WE, Simoens S. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013;28(10):2677-85.
5. Hudelist G, Fritzer N, Thomas A, Niehues C, Oppelt P, Haas D, Tammaa A, et al. Diagnostic delay for endometriosis in Austria and Germany: causes and possible consequences. Human Reprod. 2012 Dec 1;27(12):3412-6. 6) Jenkins TR, Liu CY, White J. Does response to hormonal therapy predict presence or absence of endometriosis. Journal of minimally invasive gynecology. 2008 Jan 1;15(1):82-6.
6. Vercellini P, Trespidi L, Colombo A, Vendola N, Marchini M, Crosignani PG. A gonadotropin-releasing hormone agonist versus a low-dose oral contraceptive for pelvic pain associated with endometriosis. Fertility and sterility. 1993 Jul 1;60(1):75- 9.
7. Brown J, Kives S, Akhtar M. Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database of Systematic Reviews. 2012(3).
8. Tiwari AK, Shah H, Rajpoot A, Singhal M. Formulation and in-vitro evaluation of immediate release tablets of drotaverine HCL. Journal of Chemical and Pharmaceutical Research. 2011;3(4):333-41.
9. Remington JP. Remington: The science and practice of pharmacy. Lippincott Williams & Wilkins; 2006
10. Lachman L, Lieberman HA, Kanig JL. The theory and practice of industrial pharmacy. Lea &Febiger; 1986.
11. Ansel HC, Popovich NG, Allen LV. Pharmaceutical dosage forms and drug delivery systems. Baltimore: Williams & Wilkins; 1995 Jan.
12. Aulton M, Summers M. Tablet and Compaction in: Pharmaceutics The Science of Dosage Form Design. 2 nd. Churchill Livingstone: Philadelphia. 2002:397-439.
13. Turkoglu M, Sakr A. Tablet dosage forms. InModern Pharmaceutics Volume 1 2009 May 28 (pp. 499-516). CRC Press.
14. Levin M. Granulation: endpoint determination and scale-up. Encyclopedia of pharmaceutical technology. 2007:4078-98.
15. Kiekens F, Zelkó R, Remon JP. Influence of drying temperature and granulation liquid viscosity on the inter-and intragranular drug migration in tray-dried granules and compacts. Pharmaceutical development and technology. 2000 Jan 1;5(1):131-7.
16. Shi L, Feng Y, Sun CC. Massing in high shear wet granulation can simultaneously improve powder flow and deteriorate powder compaction: A double-edged sword. European journal of pharmaceutical sciences. 2011 May 18;43(1-2):50-6.
17. Zhou J, Lipp R. Development Of Low-Dose Formulations Using Fluidized Bed Granulation. Formulation And Analytical Development For Low-Dose Oral Drug Products. 2009 Mar 4:63.
18. Zuurman K, Riepma KA, Bolhuis GK, Vromans H, Lerk CF. The relationship between bulk density and compactibility of lactose granulations. International journal of pharmaceutics. 1994 Feb 7;102(1-3):1-9.
19. Kamble ND, Chaudhari PS, Oswal RJ, Kshirsagar SS, Antre RV, Wagholi P. Innovations in tablet coating technology: A review. International Journal of Applied Biology and Pharmaceutical Technology. 2011;2(1):214-8.
20. Parveen S, Khinchi MP, PS CK. Recent Advancement in Tablet Coating Technology. World J Pharm Pharm Sci. 2017 Feb 16;6(4):2189-04.
21. Lippincot Williams And Wilkins. Remington’s The Science and Practice of Pharmacy. Volume-I. 21st ed. Indian Edition. 2005: 929-938.

Aulton M, Cole G, Hogan J. Pharmaceutical coating technology. Taylor & Francis; 1995 Oc