1. INTRODUCTION:

Self-Microemulsifying Drug Delivery Systems (SMEDDS) are lipid-based formulations designed to enhance the solubility and bioavailability of poorly water-soluble drugs. They consist of a mixture of lipids, surfactants, and co-surfactants that spontaneously form fine oil-in-water microemulsion droplets when exposed to aqueous fluids, such as gastrointestinal fluids. SMEDDS have gained considerable attention in pharmaceutical research and development due to their ability to improve drug absorption, increase therapeutic efficacy, and reduce inter- and intra-subject variability in drug response¹.

Self-Microemulsifying Drug Delivery Systems (SMEDDS) are advanced lipid-based formulations designed to enhance the solubility and bioavailability of poorly water-soluble drugs. These formulations consist of a mixture of lipids, surfactants, and co-surfactants that form fine oil-in-water microemulsion droplets when exposed to aqueous fluids, such as gastrointestinal fluids.

The use of SMEDDS has gained significant attention in the pharmaceutical industry due to their ability to overcome the challenges associated with poorly water-soluble drugs, which often exhibit low oral bioavailability and variable therapeutic response. By converting these drugs into SMEDDS formulations, it becomes possible to enhance their solubility and absorption, thereby improving their therapeutic efficacy and ensuring more predictable and consistent drug response².

This review serves as a valuable resource for researchers, scientists, and industry experts, providing insights that can guide the production of SMEDDS formulations with enhanced quality and reliability.

2. FORMULATION OPTIMIZATION:

2.1 Selection of Lipid Excipients:

The selection of appropriate lipid excipients is crucial in SMEDDS formulation development. Type I systems involve drug formulations dissolved in triglycerides or mixed glycerides, often derived from vegetable oils. These formulations are suitable for highly lipophilic drugs, relying on pancreatic lipase in the GI tract for digestion and absorption. They are simple, safe, and compatible with capsules.

Type II formulations, also known as SMEDDS, are mixtures of lipids and lipophilic surfactants that self-emulsify in aqueous media to form fine emulsions. They are ideal for poorly soluble drugs, offering convenient dosage forms in gelatin capsules. Type II formulations create large interfacial areas for efficient drug absorption and are stable upon dispersion. Type III formulations include hydrophilic surfactants and co-solvents like ethanol or propylene glycol. They disperse rapidly to form submicron dispersions, with type IIIB having more hydrophilic components. Type IV systems are pure surfactants or mixtures with co-solvents, offering increased drug-loading capacity and fine dispersions in water. Lipids play a significant role in solubilizing the poorly water-soluble drug and forming stable microemulsion droplets mention in Table 1. Factors to consider when selecting lipid excipients include their solubilization capacity, compatibility with other excipients, stability, and regulatory acceptance³.

Table 1. Examples of Lipid Excipients Used in SMEDDS Formulations⁴

Lipid Excipient	Description	Examples
Medium-Chain Triglycerides (MCTs)	Medium-chain triglycerides (MCTs) are lipids consisting of medium-length fatty acid chains. They are often used as co-solvents and co-surfactants in SMEDDS formulations.	Caprylic/ capric triglycerides (Miglyol 812), MCT oils (Lipocel), Neobee M-5)
Long-Chain Triglycerides (LCTs)	Long-chain triglycerides have longer fatty acid chains compared to MCTs. They are used as lipid carriers in SMEDDS.	Soybean oil, corn oil, olive oil, sunflower oil, cottonseed oil, sesame oil, castor oil, etc.
Fatty Acid (Mono- and Di-glycerides)	These are free fatty acids that can serve as co-solvents and co-surfactants in SMEDDS. They can also improve drug solubility.	Oleic acid, linoleic acid, stearic acid, palmitic acid, lauric acid, etc.
Phospholipids	Phospholipids are amphiphilic lipids consisting of a hydrophilic head and hydrophobic tail. They are used to create stable self-emulsifying systems and improve drug absorption.	Soy lecithin, egg lecithin, hydrogenated soy lecithin, etc.
Tocopherols (Vitamin E Derivatives)	Tocopherols are vitamin E derivatives that can enhance drug solubility and bioavailability. They are often used as co-surfactants.	Vitamin E TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate), vitamin E acetate, etc.
Squalene	Squalene is a natural lipid derived from sources like shark liver oil and olive oil. It can improve drug solubility and stability.	Squalene derived from shark liver oil, olive-derived squalene, plant-derived squalene, etc.

2.2 Selection of Surfactants:

Surfactants are instrumental in SMEDDS formulations, effectively reducing the interfacial tension between oil and water to enable the generation and sustenance of microemulsion droplets. This critical function is exemplified in Table 2.

Table 2. Examples of Surfactants Used in SMEDDS Formulations⁵

Surfactant	Emulsification Capacity	Examples
Polysorbates	High	Tween® 80, Tween® 20
Polyoxylglycerides	Moderate to high	Cremophor®EL, Labrasol®
Glyceryl esters	Moderate	Gelucire®
Labrasol®	Moderate

2.3 Co-solvents and Co-surfactants:

Co-solvents and co-surfactants are often incorporated into SMEDDS formulations to enhance solubility, fluidity, and stability shown in Table 3. Co-solvents, such as ethanol, propylene glycol, and PEG 400, improve drug solubility, while co-surfactants aid in microemulsion formation and stability.

Table 3. Examples of Co-solvents and Co-Surfactants Used in SMEDDS Formulations⁶

Component Type

Examples of Co-Solvents

Examples of Co-Surfactants

Co-Solvents

1. Ethanol

2. Polyethylene glycol (PEG)

3. Dimethyl sulfoxide (DMSO)

4. Glycerine

5. Oleic acid

1. Propylene glycol

2. Transcutol

3. Isopropyl myristate

4. Capryol 90

5. Labrafil M 1944 CS

6. Labrasol

7. Cremophor EL

2.4 Drug-Excipient Compatibility Studies:

Compatibility between the drug and excipients is crucial to ensure stability and prevent potential interactions that may affect drug efficacy or formulation performance shown in Table 4. Compatibility studies assess physical, chemical, and biological interactions between the drug and excipients to identify any potential issues.

Table 4. Example of Drug-Excipient Compatibility Study Parameters⁷

Parameter	Test Method	Example
Physical Appearance	Visual inspection	Check for color change, odor, and appearance
Melting Point	Differential scanning calorimetry (DSC)	Compare drug-excipient mixture with pure drug
Thermal Analysis	Thermogravimetric analysis (TGA)	Determine weight loss and decomposition
Infrared Spectroscopy (FTIR)	Fourier-transform infrared spectroscopy	Analyse chemical structure and functional groups
Differential Scanning Calorimetry	DSC	Determine melting point and enthalpy changes
X-ray Diffraction (XRD)	X-ray diffraction analysis	Assess crystallinity and polymorphism
Dissolution Rate	Dissolution testing	Measure drug release rates in different media
Chemical Compatibility	High-performance liquid chromatography (HPLC)	Assess chemical degradation or interaction
pH Solubility Studies	Solubility testing at different pH conditions	Examine solubility changes with pH
Accelerated Stability Studies	Long-term storage under stress conditions	Evaluate changes over time at elevated temp.
Compatibility with Excipient Binder	Mixing with binder excipient and testing	Assess impact on tablet integrity
Compatibility with Lubricants	Mixing with lubricant excipient and testing	Evaluate impact on tablet lubrication

2.5 Phase Diagrams:

Phase diagrams are graphical representations that illustrate the phase behavior of the components in a SMEDDS formulation depicted in Table 5. They help determine the optimal lipid/oil-surfactant-co-surfactant ratios for stable microemulsion formation. The construction of phase diagrams involves conducting titration experiments and visually observing the phase transitions shown in Fig.1.

Table 5. Example of a Phase Diagram for SMEDDS Formulation Optimization⁸

Lipid: Surfactant: Co-surfactant Ratio	Phase Behavior
1:1:1	No microemulsion
2:1:1	Formation of microemulsion
3:1:1	Formation of microemulsion
4:1:1	Formation of microemulsion
5:1:1	Phase separation

Figure 1. Phase Diagram for SMEDDS Formulation Optimization⁹

The phase diagram of a microemulsion system illustrates the relationship between the concentrations of oil, water, and surfactant. It is divided into distinct regions representing different phases within the system:

1. Microemulsion Region: This region corresponds to the phase where oil, water, and surfactant coexist, forming microemulsion droplets. The microemulsion region is desirable for achieving optimal drug solubilization, stability, and enhanced bioavailability.

2. Oil-Rich Region: In this region, the concentration of oil is high compared to water, resulting in the formation of oil droplets dispersed in a continuous oil phase. It is typically characterized by low water solubility and limited drug release.

3. Water-Rich Region: The water-rich region is characterized by high water concentration and low oil concentration. Water droplets are dispersed within a continuous aqueous phase. This region may exhibit limited drug solubility and lower drug release rates.

4. Middle Phase Region: The middle phase region lies between the microemulsion region and the oil-rich or water-rich regions. It represents a bicontinuous phase, where both oil and water droplets coexist, creating a complex interfacial structure. This region offers unique properties and can be tailored to control drug release kinetics.

5. Phase Separation Region: In this region, the oil, water, and surfactant are not in the same phase. It is characterized by the separation of oil and water into distinct phases, indicating instability and lack of uniformity.

By utilizing the phase diagram, formulators can predict the phase behavior and design microemulsion systems with desired properties. It guides the selection of appropriate compositions to achieve stable microemulsions and optimize drug delivery characteristics, such as solubility, release profile, and stability^10-11.

2.6 Mixing techniques for achieving uniformity and microemulsion formation, such as high-shear mixing and ultrasound:

The choice of mixing technique will depend on the drug, the excipients, and the desired properties of the SMEDDS formulation depicted in Table 6.

Table 6. Comparison of Mixing Techniques for SMEDDS¹²

Mixing Technique	Advantages	Disadvantages
High-shear mixing	Very effective at forming microemulsions	Can damage drug molecules
Ultrasound	Gentler than high-shear mixing	Less effective at forming microemulsions
Microfluidic techniques	Very precise and can create well-defined microemulsions	Requires specialized equipment

3. SCALE-UP CHALLENGES AND STRATEGIES FOR MAINTAINING PRODUCT QUALITY DURING SCALE-UP:

Scale-up of SMEDDS formulations presents several challenges that need to be addressed to maintain product quality. Here are some common challenges and strategies to overcome them during the scale-up process:

3.1 Variability in Raw Materials:

Challenge: Raw materials used in small-scale formulations may exhibit batch-to-batch variability, which can impact the final product quality during scale-up.

Strategy: It is important to conduct thorough characterization and qualification of raw materials, including lipids, surfactants, and co-surfactants. Establishing specifications and conducting quality control tests can help ensure consistency in raw material performance. Regular supplier audits and maintaining a good relationship with suppliers can also contribute to reliable sourcing of raw materials ^13-15.

3.2 Mixing and Homogeneity:

Challenge: Achieving consistent mixing and homogeneity becomes more challenging as the batch size increases during scale-up. Inadequate mixing can lead to poor formulation uniformity, affecting drug distribution and solubility.

Strategy: Implementing appropriate mixing techniques and equipment is crucial. Consideration should be given to factors such as mixing speed, vessel design, and impeller type. Optimization studies, including scale-up trials and validation, should be conducted to ensure uniform mixing throughout the larger-scale batches. In-line monitoring tools, such as process analytical technology (PAT), can aid in real-time assessment of mixing efficiency ^16-18.

3.3 Process Transfer and Validation:

Challenge: Transferring the manufacturing process from a small-scale laboratory setup to a larger-scale production facility introduces the risk of process variations and potential quality issues.

Strategy: A well-defined process transfer plan, including comprehensive documentation and communication between the development and manufacturing teams, is essential. Performing scale-up trials and process validation studies can help identify and address any challenges. Close collaboration between process development scientists and production engineers ensures a smooth transition and successful scale-up¹⁹.

3.4 Equipment Compatibility and Performance:

Challenge: The equipment used during scale-up may differ from the laboratory-scale setup, resulting in variations in mixing efficiency, heat transfer, and processing times.

Strategy: Selecting equipment that is compatible with the formulation requirements and scaling parameters is crucial. Performing equipment qualification and calibration ensures accurate measurements and performance. Validating the equipment's capabilities and establishing appropriate operating ranges help maintain consistency during scale-up²⁰.

3.5 Quality Control and Testing:

Challenge: Scaling up SMEDDS formulations can pose challenges in maintaining consistent quality control and testing processes. Increased batch sizes may require adjustments in sampling procedures and analytical methods.

Strategy: Develop a robust quality control plan that addresses the specific requirements of the larger-scale production. Ensure proper sampling techniques are implemented to represent the batch adequately. Validate analytical methods for accuracy, precision, and specificity in the larger-scale setting. Regularly monitor and review quality control data to detect any deviations or trends ^21.

3.6 Regulatory Compliance:

Scaling up SMEDDS formulations requires adherence to regulatory guidelines and compliance with Good Manufacturing Practices (GMP). Meeting regulatory requirements for quality, safety, and documentation becomes more critical during scale-up.

Strategy: Establish a comprehensive quality management system that encompasses all aspects of manufacturing, including documentation, training, equipment maintenance, and record-keeping. Conduct regular audits and inspections to ensure compliance with regulatory requirements. Engage regulatory experts to provide guidance and support throughout the scale-up process ^22-23.

In summary, addressing the challenges of scale-up in SMEDDS formulations requires careful planning, optimization, and adherence to quality control measures. By implementing appropriate strategies, conducting validation studies, and maintaining strong quality management practices, manufacturers can successfully scale up while ensuring consistent product quality and meeting regulatory standards²⁴. .

4. MANUFACTURING CONSIDERATIONS:

When considering large-scale manufacturing of SMEDDS (Self-Microemulsifying Drug Delivery Systems), several factors need to be taken into account regarding equipment selection and qualification. Here is a brief overview:

4.1 Equipment Selection: Choosing suitable equipment is crucial for efficient and consistent manufacturing of SMEDDS. Some key considerations include:

Mixing Equipment: Selecting appropriate mixing equipment capable of efficiently and uniformly blending the oil, surfactant, co-surfactant, and drug components to form the microemulsion. High shear mixers, such as homogenizers or high-speed mixers, are commonly used.

Filtration Equipment: Incorporating filtration equipment to remove any particulate matter or aggregates from the formulation during manufacturing processes ^25-26.

Filling and Packaging Equipment: Selecting equipment that allows for accurate filling and packaging of SMEDDS, such as automated filling machines or encapsulation systems.

Equipment Qualification: Ensuring the equipment used in large-scale manufacturing of SMEDDS is appropriately qualified is essential to maintain consistent product quality. Equipment qualification typically involves the following steps:

Installation Qualification (IQ): Verifying that the equipment is correctly installed and meets the required specifications and standards.

Operational Qualification (OQ): Establishing that the equipment operates within predefined operating ranges and parameters, ensuring consistent performance.

Performance Qualification (PQ): Demonstrating that the equipment consistently produces SMEDDS formulations of the desired quality, meeting predetermined acceptance criteria ²⁰.

4.2 Process Validation:

Validating the manufacturing process is crucial to ensure reproducibility and reliability of the SMEDDS formulation at a large scale. Process validation typically involves the following stages:

Process Design: Developing a robust and optimized manufacturing process that meets quality and regulatory requirements.

Process Qualification: Executing process validation studies to demonstrate that the manufacturing process consistently produces SMEDDS formulations meeting predetermined specifications.

Continued Process Verification: Establishing a monitoring and control system to ensure ongoing performance and reliability of the manufacturing process ^27-29.

4.3 Good Manufacturing Practices (GMP):

Adhering to GMP guidelines throughout the manufacturing process is essential to ensure product quality, safety, and compliance with regulatory standards. GMP guidelines encompass various aspects, including facility design, equipment maintenance, documentation, personnel training, and quality control procedures.

When considering large-scale manufacturing of SMEDDS, it is advisable to consult with experts in pharmaceutical manufacturing, process engineering, and regulatory compliance to ensure the selection and qualification of equipment align with the specific requirements and regulatory standards ³⁰.

5. SCALE-UP CHALLENGES:

Scale-up of SMEDDS (Self-Microemulsifying Drug Delivery Systems) from laboratory to commercial manufacturing can present several challenges. Let's explore the genuine details of the key challenges associated with scale-up:

5.1 Impact on Physical Properties and Stability:

During scale-up, changes in process parameters and equipment can impact the physical properties and stability of SMEDDS. Challenges include:

Phase Separation: SMEDDS may be prone to phase separation when scaled up due to increased batch sizes or changes in mixing dynamics. Optimization of mixing conditions and equipment is crucial to maintain the desired microemulsion structure and prevent phase separation ³⁰.

Droplet Size Distribution: Ensuring consistent droplet size distribution becomes challenging as batch sizes increase. The ability to maintain the desired particle size range throughout the scale-up process is important to preserve drug solubility and bioavailability.

Drug Loading and Homogeneity: Increasing batch sizes may affect drug loading efficiency and uniformity. Proper mixing and optimization of formulation parameters are necessary to ensure uniform drug distribution within the SMEDDS formulation.

Stability: Scale-up can introduce challenges related to the physical and chemical stability of SMEDDS. Changes in manufacturing equipment, handling procedures, or storage conditions may affect stability characteristics. Thorough stability testing is essential to assess and address stability issues during scale-up ³¹.

5.2 Uniformity in Larger Batch Sizes:

Maintaining batch-to-batch uniformity becomes increasingly challenging with larger-scale production. Challenges include:

Mixing Efficiency: Ensuring efficient mixing at larger scales can be demanding, especially for viscous formulations. Proper equipment selection, process optimization, and validation are necessary to achieve consistent mixing and uniformity.

Blending of Components: With larger batch sizes, achieving uniform blending of the oil, surfactant, co-surfactant, and drug components becomes critical. Proper equipment design, process parameters, and blending techniques should be employed to ensure uniformity.

Sampling and Analysis: Scaling up often requires adjusting sampling protocols to adequately represent the entire batch. Proper sampling techniques, representative sample collection, and robust analytical methods are vital to assess uniformity accurately ^32-33.

5.3 Cost Considerations and Optimization Strategies:

Cost-effective manufacturing is a significant consideration during scale-up. Challenges and optimization strategies include:

Raw Materials: Scaling up SMEDDS production may involve sourcing larger quantities of raw materials, which can impact cost and availability. Optimizing the formulation to reduce the amount of expensive or scarce components while maintaining efficacy is one approach.

Process Efficiency: Streamlining manufacturing processes to maximize efficiency and minimize waste is crucial for cost optimization. Continuous improvement efforts, automation, and process control systems can contribute to enhanced efficiency and reduced production costs³⁴.

Equipment and Facility: Selection of appropriate equipment and facility design that balances cost, productivity, and regulatory compliance is essential. Identifying cost-effective alternatives and optimizing equipment utilization can help reduce capital and operational expenses³⁵.

Regulatory Compliance: Ensuring compliance with regulatory requirements and quality standards throughout scale-up is vital. Early engagement with regulatory authorities and following regulatory guidelines can help prevent costly delays and rework.

Addressing scale-up challenges for SMEDDS requires a comprehensive understanding of formulation science, process engineering, and regulatory considerations. Collaboration among formulation scientists, process engineers, quality experts, and regulatory professionals is key to successfully navigate the scale-up process while maintaining product quality, stability, and cost-effectiveness ³⁶.

6. FUTURE PERSPECTIVES AND CONCLUSION:

Continuous manufacturing techniques offer improved control, reduced timelines, and heightened efficiency compared to traditional batch-based approaches. Quality by Design (QbD) principles enable the development and scaling of robust SMEDDS formulations, ensuring predefined quality attributes are prioritized. Integration of nanotechnology enhances drug solubility, bioavailability, and targeted delivery, leading to better therapeutic efficacy. Advanced characterization techniques like cryo-TEM, SAXS, and NMR optimize SMEDDS formulations by providing detailed insights into structure and behavior. Process Analytical Technology (PAT) tools revolutionize monitoring and control during manufacturing, ensuring consistent product quality. Personalized medicine drives the development of precision SMEDDS formulations tailored to individual patient needs, reflecting a shift towards targeted treatments. Efficient scale-up and manufacturing processes are essential for commercializing SMEDDS, ensuring product efficacy and regulatory compliance, and enabling improved patient access and therapeutic outcomes.

7. REFERENCES:

1. Prajapati AP, Patel PS, Vadgama NS, Narkhede S, Luhar S, Gandhi SJ. Formulation development and evaluation of solid self microemulsifying drug delivery system of azelnidipine. International Journal of Pharmacy and Pharmaceutical Sciences. 2023; 15(3):237-249. doi:10.25004/IJPSDR.2023.150303.

2. Ghadge Dhairyasheel, Yadav Adhikrao, Gharge Varsha. Design and development of solid self-microemulsifying drug delivery of gefitinib. Asian Journal of Pharmaceutical Technology. 2018; 8(4):193-199.

3. Vishwas R Potphode, Amol S Deshmukh, Vijay R Mahajan. Self-micro emulsifying drug delivery system: an approach for enhancement of bioavailability of poorly water-soluble drugs. Asian Journal of Pharmaceutical Technology. 2016; 6(3):159-168.

4. Pratiksha Sonawale, Amol Patil, Asmit Kamble, Mangesh Bhutkar. Solubility enhancement of lipophilic drugs- solid self-micro-emulsifying drug delivery system. Asian Journal of Pharmaceutical Technology. 2016; 6(3):155-158.

5. Dhiraj A Khairnar, Avinash B Darekar, Ravindra B Saudagar. A review on self- micro emulsifying drug delivery system: evident to improve the oral bioavailability of hydrophobic drugs. Asian Journal of Pharmaceutical Technology. 2016; 6(2):131-134.

6. Gursoy RN, Ozge C. Design, characterization and in vitro evaluation of SMEDDS containing an anticancer peptide, linear LyP-1. Pharmaceutical Development and Technology. 2014; 19(4):486-490. doi:10.3109/10837450.2013.795170.

7. Hyma Ponnaganti A, Abbulu K. Enhanced dissolution of repaglinide: SMEDDS formulation and in-vitro evaluation. Research Journal of Pharmacy and Technology. 2014; 7(11):1246-1252.

8. Patil VRM. Self-emulsifying drug delivery systems (SEDDS): a brief review. Research Journal of Pharmaceutical Dosage Form and Technology. 2014; 6(2):134-139.

9. Rahman MA, Hussain A, Hussain MS, et al. Role of excipients in successful development of self-emulsifying/microemulsifying drug delivery system (SEDDS/SMEDDS). Drug Development and Industrial Pharmacy. 2013; 39(1):1-19. doi:10.3109/03639045.2012.660949.

10. Arpana A, Kiran D, Jaydeep P, et al. An Integrated QbD Based Approach of SMEDDS And Liquisolid Compacts to Simultaneously Improve the Solubility and Processability of Hydrochlorthiazide. Journal of Drug Delivery Science and Technology. 2021; 61:1–48. https://doi.org/10.1016/j.jddst.2020.10216.

11. Foram J, Vaishali L. Solubility Enhancement of Lurasidone Hydrochloride by Preparing SMEDDS. International Journal of Pharmacy and Pharmaceutical Sciences. 2015; 7(11):283–288.

12. Jill BS, Girish KJ, Abdel W, et al. Formulation and Evaluation of Oral Self Microemulsifying Drug Delivery System of Candesartan Cilexetil. International Journal of Pharmacy and Pharmaceutical Sciences. 2016; 8(5):238–243.

13. Warke S, Warke P. Formulation Design and Evaluation of Self Micro Emulsifying Drug Delivery System. Research Journal of Pharmaceutical Dosage Forms and Technology. 2020; 12(2):58-62.

14. Deshmukh A, Jagdale A, Kulkarni S. Formulation Development and In-vitro Evaluation of Self Micro-emulsifying Drug Delivery system (SMEDDS) of Antiretroviral. Research Journal of Pharmaceutical Technology. 2012; 5(10):1347-1351.

15. Khansili A, Bajpai M. Formulation, Evaluation and Characterization of Solid Self-Micro Emulsifying Drug Delivery System (Solid SMEDDS) containing Nifedipine. Research Journal of Pharmaceutical Technology. 2013; 6(3):278-284.

16. Barber BW, Dumont C, Caisse P, Simon GP, Boyd BJ. A 3D-printed polymer–lipid-hybrid tablet towards the development of bespoke SMEDDS formulations. Pharmaceutics. 2021; 13(12):2107.

17. Patil P, Mahajan VR. Self-emulsifying drug delivery systems (SEDDS): a brief review. Research Journal of Pharmaceutical Dosage Form and Technology. 2014; 6(2):134-139.

18. Kanoujia K, Dewangan C, Masih A, et al. Self microemulsifying drug delivery system (SMEDDS): a novel approach to improve the therapeutic efficacy of orally administered drug. Research Journal of Pharmaceutical Dosage Form and Technology. 2018; 10(2):95-102.

19. Aparna K, Meenakshi B. Formulation, evaluation and characterization of solid self-micro emulsifying drug delivery system (solid SMEDDS) containing nifedipine. Research Journal of Pharmaceutical Technology. 2013; 6(3):278-284.

20. Verma R, Mittal V, Kaushik D. Quality based design approach for improving oral bioavailability of valsartan loaded SMEDDS and study of impact of lipolysis on the drug diffusion. Drug Delivery Letters. 2018; 8(2):130-139.

21. Ansari KA, Pagar KP, Anwar S, Vavia PR. Design and optimization of self-microemulsifying drug delivery system (SMEDDS) of felodipine for chronotherapeutic application. Brazilian Journal of Pharmaceutical Sciences. 2014; 50:203-212.

22. Rahman MA, Hussain A, Hussain MS, Mirza MA, Iqbal Z. Role of excipients in successful development of self-emulsifying/microemulsifying drug delivery system (SEDDS/SMEDDS). Drug Development and Industrial Pharmacy. 2013; 39(1):1-19.

23. Pouton CW, Porter CJ. Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies. Advanced Drug Delivery Reviews. 2008; 60(6):625-637.

24. Sun M, Si L, Zhai X, Fan Z, Ma Y, Zhang R, Yang X. The influence of co-solvents on the stability and bioavailability of rapamycin formulated in self-microemulsifying drug delivery systems. Drug Development and Industrial Pharmacy. 2011; 37(8):986-994.

25. Maurya SD, Arya RK, Rajpal G, Dhakar RC. Self-microemulsifying drug delivery systems (SMEDDS): a review on physico-chemical and biopharmaceutical aspects. Journal of Drug Delivery and Therapeutics. 2017; 7(3):55-65.

26. Singh AK, Chaurasiya A, Singh M, Upadhyay SC, Mukherjee R, Khar RK. Exemestane loaded self-microemulsifying drug delivery system (SMEDDS): development and optimization. AAPS PharmSciTech. 2008; 9:628-634.

27. Patel AR, Vavia PR. Preparation and in vivo evaluation of SMEDDS (self-microemulsifying drug delivery system) containing fenofibrate. AAPS Journal. 2007; 9: E344-E352.

28. Holm R, Jensen IHM, Sonnergaard J. Optimization of self-microemulsifying drug delivery systems (SMEDDS) using a D-optimal design and the desirability function. Drug Development and Industrial Pharmacy. 2006; 32(9):1025-1032.

29. Sprunk A, Strachan CJ, Graf A. Rational formulation development and in vitro assessment of SMEDDS for oral delivery of poorly water-soluble drugs. European Journal of Pharmaceutical Sciences. 2012; 46(5):508-515.

30. Cui J, Yu B, Zhao Y, Zhu W, Li H, Lou H, Zhai G. Enhancement of oral absorption of curcumin by self-microemulsifying drug delivery systems. International Journal of Pharmaceutics. 2009; 371(1-2):148-155.

31. Tung NT, Tran CS, Nguyen HA, Nguyen TL, Chi SC, Nguyen DD. Development of solidified self-microemulsifying drug delivery systems containing l-tetrahydropalmatine: design of experiment approach and bioavailability comparison. International Journal of Pharmaceutics. 2018; 537(1-2):9-21.

32. Chandrakar A, Sahu B, Sahu H, Dewangan J, Kumar N, Singh R, Alexander A. Review on the formulation considerations needed to produce a stable Self microEmulsifying Drug Delivery System (SMEDDS). Research Journal of Pharmacy and Technology. 2017; 10(5):1563-1570.

33. Chandrakar A, Sahu B, Sahu H, Dewangan J, Kumar N, Singh R, Gupta R, Kumar D, Sahu B, Dewangan K, Kaushal R, Agrawal M, Tripathi DK, Ajazuddin, Alexander A. Review on the formulation considerations needed to produce a stable Self micro Emulsifying Drug Delivery System (SMEDDS). Research Journal of Pharmacy and Technology. 2017; 10(5):1563-1570.

34. Bachhav YG, Patravale VB. SMEDDS of glyburide: formulation, in vitro evaluation, and stability studies. AAPS PharmSciTech. 2009; 10:482-487.

35. Dokania S, Joshi AK. Self-microemulsifying drug delivery system (SMEDDS)–challenges and road ahead. Drug Delivery. 2015; 22(6):675-690.

36. Dhaval M, Panjwani M, Parmar R, Soniwala MM, Dudhat K, Chavda J. Application of simple lattice design and desirability function for formulating and optimizing SMEDDS of clofazimine. Journal of Pharmaceutical Innovation. 2021; 16:504-515.

Received on 17.03.2024 Modified on 20.05.2024

Res. J. Pharma. Dosage Forms and Tech.2024; 16(3):261-267.

DOI: 10.52711/0975-4377.2024.00041