PHARMACEUTICAL APPLICATIONS OF LYOPHILIZATION: RECENT UPDATES AND ADVANCEMENTSHTML Full Text
PHARMACEUTICAL APPLICATIONS OF LYOPHILIZATION: RECENT UPDATES AND ADVANCEMENTS
M. S. Motwani, A. R. Shahu, M. J. Umekar, D. M. Biyani and K. J. Wadher *
Department of Pharmaceutics, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India.
ABSTRACT: For almost five decades, from its application in preserving blood plasma to stabilizing pharmaceuticals and biopharmaceuticals, lyophilization has been used in life sciences. Lyophilization is a popular drying technique for preserving various drugs, formulations and biological materials such as proteins, plasma, and living cells. The researchers have made significant efforts to develop lyophilized nanoparticulate drug delivery formulations. During lyophilization, biological products and vaccines could be increased by removing solvents and the shelf-life of injectables. Thus, lyophilization unstable or heat-sensitive drugs/biologicals can be dried at low temperatures without damaging their physical structure. Lyophilized products can be reconstituted quickly and easily, improving shelf life and easy transportation. Vast applications of lyophilization in the Pharmaceutical Area established the importance of lyophilization techniques in the pharmaceutical field. The present review aims to update recent and advanced applications of Lyophilization techniques in Pharmaceuticals and biological products such as Antibiotics, Vaccines, proteins, enzymes, and hormones.
Keywords: Lyophilization, Freeze drying, Pharmaceuticals, Vaccine, Nanoparticles
INTRODUCTION: Long-term stability of formulations plays a crucial role in designing any drug delivery system. Formulators face chemical and physical instability during the formulation and storage of formulations. Drying is one of the popular methods for the preservation of drugs as well as formulation to prevail over these instabilities. Drying is one of the basic unit operations in pharmaceutical industries, permitting the removal of solvents from liquid drug formulations to transit them into solid forms.
Lyophilization (freeze drying), a water removal method that involves the freezing and drying process, is well established and helps improve the stability of various drugs/formulations 1. Lyophilization is considered to be the most accepted drying process for manufacturing pharmaceutical products that are thermo labile and unstable in an aqueous medium to provide stability.
Lyophilization offers many advantages over other drying processes, such as temperatures used during this process, the freeze-dried product's shelf life, reconstitution and the aseptic processing operation. Recent years witnessed the popularity of various novel techniques for the formulation and stabilization of various drugs, formulations, and biological materials such as proteins, plasma, and living cells, as well as nano drug delivery carriers such as liposomes, niosomes, exosomes, nanoparticles 3, 4. In addition, dry nano-formulations, enzymes and DNA-based formulations could be made via lyophilization, which improves long-term storage and helps avoid costly and tedious cold chain transportation 5, 6, 7. This is a popular drying technique in developing solid-state protein therapeutics compared to liquid protein formulations because lyophilized proteins can overcome storage stability issues and are more convenient for transportation and delivery 8, 9. Over the last ten years, the use of lyophilization in pharmaceutical and biopharmaceutical industries has escalated at a rate of more than 14 percent annually. Lyophilization is especially useful for parenterals formulations as the stable injectable reconstituted powder can be easily packaged and transferred as a finished drug product. This technique can also be used to generate stable intermediates in the development and manufacturing of pharmaceutical products 10.
Many researchers and pharmaceutical industries worked on developing and stabilizing Injectable, reconstituted powders and nano-delivery products. The various application of lyophilization as depicted in Fig. 1 and Table 1.
FIG. 1: APPLICATION OF LYOPHILIZATION IN PHARMACEUTICALS
TABLE 1: APPLICATION OF LYOPHILIZATION IN PHARMACEUTICALS
|Acetazolamide11 (US20150061169A1)||Injection||Anti-glaucoma||Increases stability for longer period.|
|Acetylcystein 12 (CN101239037B)||Injection||Mucolytic & Antidote||Stable after being stored for a long period|
|Acyclovir13 (CN101897672A)||Injection||Antiviral||Increases stability,faster dissolution|
|Amphotericin B14||Injection||Antifungal||Increases solubility and stability|
|Ambisome15||Liposome for injection||Fungal infection||Increased shelf life up to 36 months|
|Artesunate 16 (CN103705475A)||Injection||Antimalarial||Increases solubility and good stability|
|Azithromycin 17 US7468428B2)||Injection||Antibacterial, Antibiotic||Increases Stability|
|Bortezomib18 (CN110314221B)||Injection||Cancer||Improves solubility and stability|
|Caspofungin19 (EP 2 922 530 B1)||Injectable powder||Antifungal||Improves long-term stability|
|Chlorpheniramine20 (Dave, Vivek et al 2016)||Tablet||Allergic rhinitis||Rapid dissolution|
|Clarithromycin21 (CN104586791A)||Tablet||Antibiotic||Improves dissolution and bioavailability|
|Colistimethate||Injection||Antibiotic||Improves stability at a storage|
|Decitabine22 (WO2013093934A1)||Injection||Myelodysplastic Syndrome||Increases stability|
|Dobutamin23 (CN104706572A)||Injection||Cardiac||Improves stability for long term|
|Epirubecin24 (CN103006586A)||Injectable||Anticancer||Improves patient drug safety and stability|
|Erythomycin25 (CN104819622A)||Injection||Antibiotic||Improve stability|
|Esmoprazole26 (CN102657650A)||Injection||Anti-Ulcer (Proton Pump Inhibitor)||Improves stability at a storage|
|FluphenezineDecanoate||Injection||Antipsychotic||Improves stability at storage|
|Flutamide27||Dispersion||Cancer||Increased dissolution rate|
|Gemcitabine28 (CN102302462A)||Powder||Antibiotic||Improves stability|
|Glanciclovir29 (CN104666303A)||Injection||Antiviral||Efficiency of product is increased|
|Glyburide30 (CN104490755A)||Tablet||Hypoglycemic agent||Increased solubility|
|Haloperidol Decanoate||Injection||Antipsychotic||Increase the stability of formulation|
|Hydralazin||Injection||Cardiac||Increase the stability of formulation|
|Itraconazole31 (CN102499909A)||Nanosphere||Fungal infection||Increase the stability of formulation|
|Ketamine||Injection||Anaesthetic||Increase the stability of formulation|
|Ketoprofen32 (CN1264505C)||Injection||NSAID||Improves solubility and stability|
|Lansoprazole33 (CN102302463A)||Injection||Anti-Ulcer (Proton Pump Inhibitor)||Improves solubility of insoluble particles|
|Lignocaine34 (CN105663105A)||Injection||Anaesthetic||Improve stability|
|Lornoxicam35 (CN101327193A)||Injection||NSAID||Great improvement in stability|
|Olanzapine36 (EP1423124B1)||Injection||Antipsychotic||Improves stability|
|Omeprazole37 (CN102512380B)||Powder injection||Anti-Ulcer (Proton Pump Inhibitor)||Excellent stability|
|Pantoptazole38 (WO2009001163A1)||Injection||Anti-Ulcer (Proton Pump Inhibitor)||Good stabilty|
|Paclitaxel39 (CN105055341A)||Dispersion||Cancer||Increase the stability|
|Pembrolizumab40||Injection||IgE Antibodies||Improves proyein stability|
|Pemetrexed41 (CN105726492A)||Powder injection||Anti tumor||Good stability, good redissolution|
|Polymyxin B42||Powder||Antibiotic||Increases stability up 12 months|
|Rabeprazole43 (CN102552178B)||Injection||Anti-Ulcer (Proton Pump Inhibitor)||Increase solubility and stability|
|Remdesivir||Powder||Antiviral||Increase the stability of formulation|
|Resperidone44||Nanosuspension||Psychotic disorder||Increased the physical stability|
|Rifampacin45 (CN103976959A)||Injection||Anti-Tubercular Antibiotic||Increases stability and shelf life|
|Rocuronium46 (CN1864667B)||Injection||Muscle Relaxant||Improves stability at storage|
|Sodium aescinate47 (CN102836133A)||Powder injection||Antiinflamatory||Increases stability|
|Sirolimus48||Liposomes||Organ transplant rejection||Increased shelf life|
|Succinylcholine||Injection||Muscle Relaxant||Increase the stability of formulation|
|Thiopental||Injection||Anaesthetic||Increase the stability of formulation|
|Thiotepa49 (EP0656211A1)||Injection||Anti tumor||Improves stability|
|Vancomycin50 (US4885275A)||Injection||Antibiotic||Provides stability and increases solubility|
|Vecuronium51 (CN103520121B)||Injection||Muscle Relaxant||Provides good stability|
|Voriconazole52 (CN103251565A)||Injection||Antifungal||Improves solubility and stability|
|Zoledronic Acid53 (CN102372741B)||Injection||Calcium Regulator||Increases stability|
Nanoparticulate System: Nanoparticles have received much attention in the therapeutics field over the last few decades especially in imaging, sensing gene delivery systems, and novel drug delivery. Significant efforts have been made to develop nanoparticulate systems for drug delivery (e.g., polyplexes, vaccines, and liposomes) 54. This freeze-drying technique is frequently used as a primary strategy for reducing stability risks and increasing the shelf life of liposome-based drugs 55, 56. Liposomal instability is a major drawback in developing a liposomal formulation for clinical use, and lyophilisation could be the better strategy for increasing liposomal product shelf life. Lyophilized drug product designs (e.g. lyo-product, lyo-cake) facilitate liposomal storage in dry state forms, extending shelf life and reducing cold chain custodial demands 57, 58. Mohammady M. et al; elucidated the importance of various parameters involved in freeze-drying for the most common pharmaceutical NPs which include nanosuspensions, nanocrystals (NCs), cocrystals/ nanococrystals, nanoemulsions (NEs), nanocapsules (NCPs) and nanospheres (NSPs). They concluded that lyophilization could be used for developing different types of NPs like nanotubes, nanofibers, and nanoaggregates on an industrial scale 59 Rouquette, M. et al.; developed Squalene-adenosine (SQAd) NPs. Due to various long term stability issues these nanoparticles were lyophilised and the Long-term stability was found to be better for the prepared Nanoparticles 60. Fonte P et al. evaluated the influence of a freeze-drying process using different cryoprotectants on the structure of insulin loaded into poly (lactic-co-glycolic acid) nanoparticles and assessed the stability of these nanoparticles. They observed a marked improvement in the structural stability of insulin after the freeze-drying process 61. Charoenviriyakul C. et al., developed exosomes using lyophilization as preservation of exosomes is stable at -80 °C. The researchers concluded lyophilization to be an effective method for storing exosomes 62. Xie C. et al.; used a polymerization-induced aramid nanofiber as a building block which helped modify the freeze-drying method for the preparation of para-aromatic-amide aerogels 63.
Luo, W. C. et al; evaluated the effects of freeze drying on solid lipid nanoparticles (SLNs), polymeric nanoparticles (PNs), and liposomes. They concluded that freeze drying increased the stability and quality of freeze-dried nanoparticles 64 Trenkenschuh, E., et al.; reviewed the stresses that occurred during the freezing and the drying step of lyophilization of polymeric, or vesicular Nanoparticles, and they formed NP lyophilizes which showed excellent colloidal stability 65. Gandhi, N. V. et al.; developed a nanoparticulate (nanocrystals-loaded) or dispersible tablet with improved solubility and bioavailability. This study concluded that the prepared Nano sized Nitrendipime increased solubility and bioavailability 66.
Khattab, W. M. et al.; demonstrated the enhancement in oral bioavailability of a poor water-soluble antihypertensive drug Olmesartan Medoxomil (OM), due to the formulation of lyophilized oily-core nanocapsules. A comparative study of pharmacokinetics in rats was performed for oily-core polymeric nanocapsules after formulation, and the lyophilization tablet showed a significant improvement in oral absorption of OM. This concluded that the formulation of lyophilized ONC for OM had significantly enhanced oral bioavailability, therapeutic efficacy, and patient compliance 67. Mohammed, A. R. et al. investigated various liposomal vaccine techniques so that they can be prepared in a freeze-dried state. They concluded the improvement in the long-term stability of liposomal vaccines by formulating freeze-dried products 68. Wang, Y. et al.; reviewed an overview of liposome formulation-specific lyophilization approaches for parenteral use. They concluded that lyophilization methods preserve liposome formulation stability and product shelf-life 69. Howard, M. D. et al.; optimized a lyophilization process for solid–lipid nanoparticles (SLNs) loaded with dexamethasone palmitate (Dex-P). They also compared the long-term stability of lyophilized SLNs and aqueous SLN suspensions at two different storage conditions. The results concluded that the lyophilized SLNs stored at 4°C exhibited the greatest stability, with no change in the particle size 70.
Muramatsu, H. et al; demonstrated that nucleoside-modified mRNA- LNPs could be lyophilized, with no significant change in properties for 12 weeks after storage at room temperature and at least 24 weeks after storage at 4°C. This study concluded a potential solution to overcome the long-term storage-related limitations of nucleoside-modified mRNA-LNP vaccines by lyophilization 71. Hamaly, M. A., et al.; evaluated the colloidal stability of gold nanorods (GNRs) conjugated with rituximab as a model monoclonal antibody upon freeze-drying in the presence of various cryoprotectants (mannitol, trehalose, and sucrose. The researchers also concluded that Lyophilized Rituximab conjugated GNRs preserve typical lymphoma tissue binding 72.
Wong, C. Y. et al., fabricated nanoparticles containing cationic chitosan and anionic Dz13Scr (Dz13 is a polyanionic oligonucleotide (DNAzyme)) using complex coacervation and lyophilized to preserve the bioactivity of entrapped insulin and they concluded that the stability of drug delivery system against enzymes was improved by entrapment of insulin within lyophilized nanoparticles 73. Pena-Rodríguez, E. et al.; developed a Dexamethasone-loaded polymer hybrid Nanoparticles to treat alopecia areata. The lyophilized nanoparticles showed better resuspension and acceptable physicochemical parameters 74 Wang et al. reviewed about design strategies of lyophilized liposome-based parenteral drug development. Lipid nanoparticle (LNP)-formulated nucleoside-modified mRNA vaccines have proven to be extremely effective in combating the coronavirus disease 2019 (COVID-19) pandemic due to their safety. However, long-term storage of mRNA-LNP vaccines without freezing remains a challenge. The study showed that nucleoside-modified mRNA-LNPs could be lyophilized and that the physicochemical properties of the lyophilized material do not change significantly after 12 weeks of storage at room temperature and at least 24 weeks of storage at 4°C. These mRNA-LNP vaccines were observed for 12 weeks of room temperature storage or at least 24 weeks after storage at 4°C. This finding suggested a potential solution to the long-term storage limitations of nucleoside-modified mRNA-LNP vaccine and can be transported easily 75.
Vaccines: Vaccination for disease prevention was first proposed in the late 1800s, and vaccines against tuberculosis, yellow fever, and influenza had been developed by the early 1900s. Vaccine liquid formulations are susceptible to instabilities caused by various physical and chemical degradation processes. Using the Lyophilisation method, various degradation pathways can be avoided or prevented in dried formulations.76 Recently; vaccines are mostly developed as lyophilized or aqueous formulations; due to necessitates storage at sub-ambient temperatures and the inherent lack of vaccine thermostability to overcome these storage requirements in the developing world can be difficult; therefore, vaccines are frequently exposed to temperatures that cause vaccine efficacy losses.
Preston, K. B. et al., described the development and characterization of monovalent and trivalent filovirus vaccines with a squalanein-water emulsion adjuvant. After lyophilization and reconstitution, they found that the adjuvant particle diameter and zeta potential were preserved in the single-vial presentation. Further, they concluded that these findings promote the development of a single-vial trivalent filovirus vaccine, which would make vaccine distribution and administration in resource-constrained places easier 77. Preston, K. B. et al., reviewed variously lyophilized and spray-dried vaccines for various pathogens, as well as some of the assays, were used to quantify their stability.. Recent trends include needle-free dry powder delivery via nonparenteral administration methods and the introduction of improved vaccine adjuvants into formulations. They concluded that lyophilization and spray drying are the most common methods of stabilizing vaccines through drying 78. Ameri, M. et al.; Formulated trivalent influenza split vaccine at high concentration and it was coated on the transdermal microneedle system. In this study, they used three influenza strains, out of which two influenza A strains and one influenza B strain which was then diafiltrated, concentrated and lyophilized as a monovalent vaccine. This study revealed that the transdermal microneedle technology is an appealing alternative for influenza vaccine delivery, with major benefits such as preservative-free storage and storage at room temperature 79.
Hammerling, M. J. et al.; studied and compared lab-developed and commercial SARS-CoV-2 diagnostic RT qPCR mixes for the ability to be lyophilized and thus stabilized against high temperatures. This comparison concluded that the commercial mix had maintained activity and sensitivity after storage for at least 30 days at ambient temperature after lyophilization 80.
Dry Powders: Pulmonary delivery is promising for treating many lung diseases, including Cystic fibrosis because it allows for noninvasive and direct drug deposition in the lungs. Lyophilisation was used to convert them to dry powders in order to improve the stability of nasal delivery 81. Wanning et al.; outline the development of flowable lyophilized powders and conclude that lyophilized powder with small particle size showed significant particle size distribution for needle-free injection or nasal delivery of protein and peptides 82. Zhang et al; expressed the development of PEGylated chitosan/CRISPR-Cas9 dry powders for pulmonary delivery through thin-film freeze drying and concluded that TFFD processing of CRISPR-Cas9 polymer nanocomplexes showed higher transfection efficiency and improved the aerodynamic performance of dry powder formulations. This technique showed the encouraging way to prepare polymer-based nucleic acid nanocomplex dry powder 81. Pozzoli, M. et al.; developed an amorphous solid dispersions/solution (ASD) of a poorly soluble drug, budesonide (BUD), with a novel polymer Soluplus® (BASF, Germany) using a freeze-drying technique to improve dissolution and absorption through the nasal route 83. Liu, D et al.; performed formulation screening and freeze-drying process optimization to produce ginkgolide B (GB) lyophilized powder for injection with outstanding appearance and consistent quality. And they concluded that GB lyophilized powder for injection was prepared with improved solubility more than 18 times 84.
Li, Z. et al.; studied the effective strategies for the drug development of α9α10 Nicotinic Acetylcholine Receptor Antagonist α-Conotoxin GeXIVA. According to this study, drug development ofα9α10 Nicotinic Acetylcholine Receptor Antagonist α-ConotoxinGeXIVA for clinical use has been limited due to its instability. To overcome this instability, the drug was lyophilized, which improved the stability of the 85. Liawrungrueang, W. et al.; aimed to evaluate the elution characteristics of gentamicin-impregnated PMMA made with lyophilized liquid gentamicin, which was compared with PMMA; which was made from commercial gentamicin powder. This study concluded that the Gentamicin-impregnated PMMA made with lyophilized liquid gentamicin showed a higher rate of antibiotic elution in preliminary in vitro studies when compared with PMMA made with premixed gentamicin powder 86.
Solid Dosage Form: Orally disintegrating tablets, due to their added advantages, gained popularity amongst other solid dosage forms 87. Liu, T. et al.; formulated Meloxicam nano suspensions which were prepared using three different methods: high-pressure homogenization, wet bead milling, and a combination strategy of freeze-drying and high-pressure homogenization. According to this study, Freeze-dried meloxicam powder has highly improved the size reduction efficiency compared to the unmodified drug, and the particle size of the freeze-dried sample was reduced to 342 nm after only one homogenization cycle at 1000 bar. This study concluded that the tablets made using homogenizer nanosuspensions and a combination method disintegrated faster in the first 20 minutes than bead milling nanocrystal tablets 88. Alami-Milani, M. et al.; prepared and optimized a fast disintegrating tablet of isosorbide dinitrate using lyophilization. The results demonstrated a faster disintegration rate of the lyophilized preparation 87. Vanbillemont, B. et al; Prepared and compared Four ODTs with diverse properties using lyophilisation technique. They concluded that Orally disintegrating tablets (ODTs) produced by lyophilization have a unique porous structure which leads to a favorable orodispersable functionality. They also possess ultra-fast disintegration kinetics, with acceptable mechanical strength, and also give a smooth mouth texture 89.
Lal, M. et al. prepared fast-dissolving tablets (FDTs) using the freeze-drying in blister method and confirmed the stability of the formulations 90. Zhu, C. et al.; Reviewed that postpartum hemorrhage is a leading cause of maternal mortality and morbidity in various underdeveloped nations. They recommended treatment that includes oxytocin delivery; however, because oxytocin is a heat-labile protein, it must be administered as an intramuscular injection by trained medical personnel. So, they created a freeze-dried oxytocin fast-dissolving tablet (FDT) for needle-free sublingual (SL) delivery to solve these issues 91. Rautiola, D. et al.; demonstrated the use of avizafone (AVF), a prodrug for diazepam, as a stabilizer to reduce APB inactivation during lyophilisation. Lyophilization of the APB+AVF+trehalose formulation was subjected to a 6-month accelerated stability study, with negligible activity reduction observed at the end. They concluded that lyophilisation with substrate and trehalose provides a greater stabilizing effect 92.
Gene Therapy: Gene therapy is a method of treating disease that involves delivering gene coding or editing material. Lyophilization has been used in gene therapy to facilitate refrigerated storage of biologics that are not stable in liquid form 93. Zhang, Y. Z. et al.; created a lyophilized (freeze-dried) Adeno-associated viruses (AAV) formulation and concluded that the lyophilized formulation prepared was stable for 24 months at 2 to 8°C, which showed that a dried formulation for AAV gene therapy is feasible after lyophilization 93. Mohammed saeid et al.; suggested the in-vitro transfection of gemini surfactant-lipoplexes and the influence of lyophilization on critical physiochemical properties and also appraised the viability of lyophilization as a method for producing long-lasting lipoplexes. Furthermore, they concluded that when compared to liquid formulations, gemini surfactant-based lipoplexes were much more physically stable after lyophilization 94.
Kasper et al.; recommended lyophilization of gene carrier systems for long-term storage stability and concluded that the lyophilized products showed higher transfection efficiency and long-termed physical stability and improved shelf life of products 95.
Del Pozo-Rodriguez et al.; outline the influence of lyophilization on the morphological properties and transfection capacity of solid lipid nanoparticles (LyoSLN) and SLN-DNA vectors (Lyo(SLN-DNA)). The Researchers concluded that lyophilization can generate physically stable dried SLNs 96. Wang W. studied that developing recombinant protein pharmaceuticals proved to be very challenging because of both the protein production and purification complexity and the limited physical and chemical stability of proteins. To overcome the instability barrier, proteins often have to be made into solid forms to achieve an acceptable shelf life as pharmaceutical products. The most commonly used method for preparing solid protein pharmaceuticals is lyophilization (freeze-drying). This concluded that lyophilization has efficient and minimal adverse effects on protein stability 97.
Inserts, Needles and Microneedles: Abdelmonem, R. et al.; formulated a novel Bioadhesive granisetron hydrochloride (GH) spanlasticin gels and inserts. They lyophilized the prepared inserts for intranasal delivery, thereby increasing GH bioavailability and brain targeting for the prepared bioadhesive 98. Sabri, A. et al.; presented the development of a composite pharmaceutical system that was composed of hydrogel-forming microneedles (MNs) in tandem with CFZ dry reservoirs. They created two distinct CFZ-loaded dry reservoirs, which were then evaluated based on directly compressed tablets (DCT) and lyophilized (LYO) wafers. They concluded that the dry reservoir systems showed fast dissolution, dissolving in phosphate buffer saline pH 7.4 in less than one minute 99.
CONCLUSION: This review concluded that lyophilization in the pharmaceutical formulation had gained major advantages for improving the stability, storage, and making transportation easy for Pharmaceuticals. The Lyophilization technique can generate physically stable dried pharmaceutical formulations, including solid lipid nanocarriers, parenteral, vaccines, and many more. This technique could also improve the dissolution of reconstituted productalong by efficiently processing a liquid formulation.
ACKNOWLEDGMENT: The authors are thankful to Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, India, provides the necessary facilities.
CONFLICTS OF INTEREST: The authors declare no conflict of interest, financial or otherwise.
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How to cite this article:
Motwani MS, Shahu AR, Umekar MJ, Biyani DM and Wadher KJ: Pharmaceutical applications of lyophilization: recent updates and advancements. Int J Pharm Sci & Res 2023; 14(4): 1594-03. doi: 10.13040/IJPSR.0975-8232.14(4).1594-03.
All © 2023 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.
M. S. Motwani, A. R. Shahu, M. J. Umekar, D. M. Biyani and K. J. Wadher *
Department of Pharmaceutics, Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India.
07 July 2022
30 August 2022
20 October 2022
01 April 2023