Puneet PPT On Formulation & Evalution of Nano-Suspension of Carvedilol.pptx

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1. Rajasthan University of Health Sciences, Jaipur (Rajasthan) In partial fulfillment for the award of the degree of Master of Pharmacy in Pharmaceutics A thesis presentation synopsis submitted to the Under the guidance of Supervisor: Mr. SUNIL KUMAWAT, M.Pharm Associate Professor, Department of Pharmaceutics Submitted by NAME: PUNEET KUMAR MAHARSHI Enrollment No. 2006/14512 June 2025 GOENKA COLLEGE OF PHARMACY Formulation and Evaluation of Nanosuspension of Carvedilol

2. Nanosuspension are aqueous suspensions containing one or several submicron colloidal system which consists of poorly water-soluble drug, suspended in an appropriate dispersion medium stabilized by surfactants and also contain appropriate stabilizers. stabilizer can added to reduce the free energy of the system by decreasing interfacial tension and to prevent nanoparticle aggregation by electrostatic or steric stabilization. Stabilizer constitutes an integral part of nanosuspensions and it is important to understand their role on physical stability of nanosuspension . Stabilizers include excipients that enable nanogrinding of the drug particles, prevent crystal growth or nanoparticle aggregation during storage, pH-buffering substances, and preservatives. Commonly used polymeric stabilizers for nanosuspensions include cellulose ethers, such as hydroxyl propyl cellulose (HPC) and hydroxyl propyl methylcellulose (HPMC), povidone , and poloxamers (types 188, 407 and 338). 1. Introduction of Nanosuspension

3. Advantages of Nanosuspension: Enhance the solubility and bioavailability of drugs Suitable for hydrophilic drugs Higher drug loading can be achieved Dose reduction is possible Enhance the physical and chemical stability of drugs Provides a passive drug targetes Provides ease of manufacture and scale-up for large scale production. Long-term physical stability due to the presence of stabilizers. Rapid dissolution and tissue targeting can be achieved by IV route of administration, Reduction in tissue irritation in case of subcutaneous/intramuscular administration. Higher bioavailability in case of ocular administration and inhalation delivery. Drugs with high log P value can be formulated as nanosuspensions to increase the bioavailability of such drugs

4. Biopharmaceutics Classification System For the most part, the instant release (IR) solid oral dosage forms were the primary focus of the development of the biopharmaceutical categorization system. In the scientific community, it is the framework for categorizing pharmacological compounds according to their permeability to the digestive tract and their capacity to dissolve in water. 7 It is a technique for the development of drugs that enables evaluation of the contributions of three important parameters, namely dissolution, solubility, and intestinal permeability, which have an effect on the oral drug absorption from quick release solid oral dosage forms. There is a significant amount of interest in this categorization system primarily due to the fact that it can be utilized in the early stages of medication development and subsequently in the management of product modification throughout the cycle of its life. The guideline paper on immediate release solid oral dosage forms was the first place where it was incorporated into the process of making decisions on regulatory compliance: Adjustments made after approval and scaling up. 8

5. Rational of developing drug nanosuspensions There is a lack of efficiency in the present methods used to create new pharmaceutical goods. There are around 250 compounds that make it into the preclinical program for every 5,000–10,000 molecules that enter the R&D pipeline. Out of those, five make it into clinical trials, and only one is approved for market introduction. The primary causes of expenses, which can vary from 0.8 to 2 billion dollars, are the failure of a novel molecule at the late pre-clinical stage and the growing costs of phases 1 to 3 of clinical trials. These factors contribute to the overall expense of bringing a new therapeutic substance to market. A pharmaceutical product must meet the current standards of health regulatory agencies throughout its development, from discovery to marketing and post-marketing. Pharmaceutics must have constant important quality qualities such dosage consistency, drug solubility, and storage stability, as well as a stable and robust production process, to guarantee quality, effectiveness, and safety. New molecule synthesis and in vitro bioactivity testing have been considerably accelerated by the increased use of combinatorial chemistry, phage display libraries, and high-throughput screening.

6. Methods of Preparation For Nanosuspensions : A. Milling techniques ( Nanocrystals or Nanosystems ) Media milling: Media milling is a method that is utilized in the process of preparing nanosuspensions . 19 Nanocrystal is a technology that was invented by Liversidge and colleagues and is protected by a patent. The medication is milled through a medium in this method, which results in the formation of nanoparticles of the targeted substance. The microparticulate drug is disintegrated into nanosized particles with the application of high energy and shear forces that are created as a consequence of impaction of the milling media with the drug. This provides the necessary energy input. During the process of media milling, the milling chamber is loaded with the milling medium, water or an appropriate buffer, the medication, and the stabilizer. In the following step, the milling medium or pearls are spun at a shear rate that is extremely high. The most significant issue that arises with this approach is the possibility that the grinding medium residues that are left behind in the final product might cause difficulties in terms of administration. 19

7. B. Dry co-grinding: Wet grinding procedures include the preparation of nanosuspensions by high pressure homogenization and media milling using a pearl-ball mill. Nanosuspensions have recently been able to be created through the use of dry milling processes. Following dispersion in a liquid medium, it has been reported that successful work has been done in the manufacture of stable nanosuspensions by the use of dry-grinding of weakly soluble medicines coupled with soluble polymers and copolymers. (41–42 ) Grinding with polyvinyl pyrrolidone (PVP) and sodium dodecyl sulfate (SDS) resulted in the development of colloidal particles of a number of medications that are not very water soluble. These pharmaceuticals include griseofulvin , glibenclamide , and nifedipine . Itoh et al. described the formation of these colloidal particles. There have been a great number of soluble polymers and co-polymers utilized, including polyvinyl alcohol (PVP), polyethylene glycol (PEG), hydroxyl propyl methylcellulose (HPMC), and derivatives of cyclo -dextrin. 35–37

8. C. Precipitation Method: The medication is dissolved in an organic solvent and then combined with a miscible anti-solvent using a precipitation process. The medication precipitates out of water-solvent mixtures due to its poor solubility. There is a wide range of mixing procedures. There has also been a combination of strong shear processing with precipitation. The nanoedge method, which is owned by Baxter International Inc. and its subsidiaries, uses high shear and/or heat energy to precipitate friable materials, which are then fragmented.

9. D. Supercritical fluid method: Nanoparticles can be manufactured from pharmaceutical solutions using supercritical fluid technology. The many approaches that were tried out included the supercritical anti-solvent process, precipitation with compressed anti-solvent, and rapid expansion of supercritical solution (RESS). As the drug solution in supercritical fluid is forced to expand via a nozzle in the RESS, the solvent power of the fluid is reduced, and the drug is precipitated as small particles. The PCA approach involves atomizing the medication solution and then placing it in a chamber with pressurized carbon dioxide. The solution becomes supersaturated upon solvent removal, leading to the precipitation of fine crystals 144. In the supercritical anti-solvent procedure, a medication that is not very soluble in a supercritical fluid is combined with a solvent that is both miscible with the fluid. After being injected into the supercritical fluid, the drug solution becomes supersaturated as the solvent is removed by the fluid. Fine crystals of the substance are then precipitated.

10. E. Post-Production Processing: When the drug candidate is very vulnerable to hydrolytic cleavage or chemical degradation, post-production processing of nanosuspensions becomes a critical step in the process. Processing may also be necessary in situations when the nanosuspension cannot be stabilized for an extended period of time using the best feasible stabilizer, or when there are acceptability limits in relation to the route that is sought. In light of these considerations, it is possible to accomplish the production of a dry powder consisting of nano -sized drug particles by employing methods such as lyophillization or spray drying. When it comes to these unit activities, rational selection is required, taking into consideration the characteristics of the medicine as well as the cost elements.

11. Methods of Preparation For Nanosuspensions : 1. Milling techniques ( Nanocrystals or Nanosystems ) Media milling 2. Dry co-grinding 3. High Pressure Homogenization: (HPH) Homogenization in Aqueous media ( Dissocubes ) b. Homogenization in Non Aqueous Media ( Nanopure ) 4. Precipitation Method 5. Supercritical fluid method 6. Post-Production Processing

12. 2. REVIEW OF LITERATURE Aldeeb et al., (2024) nanosuspensions have emerged as a promising solution for addressing the bioavailability challenges of hydrophobic drugs with poor solubility in both aqueous and organic environments. By enhancing drug solubility and absorption, nanosuspensions offer significant potential in improving drug delivery, particularly for topical applications such as ocular, pulmonary, and dermal treatments. Among these, nanocrystals have gained attention for their ability to increase skin adhesiveness, saturation solubility, and dissolution rates, thereby improving cutaneous bioavailability for low-to-medium solubility drugs. Redon, J et al.,(2024) High blood pressure (HBP) is the leading cause of mortality and years of disability, and its prevalence is increasing. Therefore, diagnosis and effective treatment of HBP is one of the main goals to prevent and reduce its complications, and pharmacological treatment is the cornerstone of hypertension management. The gradual introduction of different drug families has led to the development of new molecules that have improved efficacy and reduced adverse effects.

13. Narla , D. et al., (2024) Orodispersible films (ODF) represent an innovative approach in drug delivery systems, offering solutions to enhance patient compliance and address challenges associated with traditional dosage forms. Particularly beneficial for patients with swallowing difficulties, ODFs can be easily ingested without the need for water, chewing, or swallowing. Carvedilol, characterized by low bioavailability due to hepatic first-pass metabolism, prompted the focus of this research on developing carvedilol ODFs to enhance its bioavailability. Zhang, M et al., (2024) This study investigated the solubility, oil–water distribution coefficient, and dissociation constant of Isoxanthohumol (IXN) and formulated IXN nanoparticles (IXN- Nps ) using micro media grinding. Characterization revealed an average particle size of 249.500 nm, a polydispersity index of 0.149, and a zeta potential of −25.210 mV. Mannitol (5%) was identified as the optimal cryoprotectant . Compared to IXN, IXN- Nps exhibited a threefold decrease in the half-maximal inhibitory concentration, significantly inhibiting HT-29 colon cancer cells.

14. Kolipaka , T et al., (2023) Posaconazole (PSZ), an anti-fungal drug, has broad-spectrum activity. But its action is limited due to the poor solubility of posaconazole . The objective of the present study was to formulate and optimize posaconazole nanosuspension using a wet milling process. Final product quality was assured by a Quality by Design ( QbD ) approach that evaluated the impact of critical material attributes (CMAs) and critical process parameters (CPPs) on the critical quality attributes (CQAs) of the nanocrystals . Chiclana et al., (2023) Carvedilol (CARV) is an ‘off-label’ β-blocker drug to treat cardiovascular diseases in children. Since CARV is nearly insoluble in water, only CARV solid forms are commercialized. Usually, CARV tablets are manipulated to prepare an extemporaneous liquid formulation for children in hospitals. We studied CARV to improve its aqueous solubility and develop an oral solution. In this study, we assessed the solubility and preliminary stability of CARV in different pH media. Using malic acid as a solubility enhancer had satisfactory results. We studied the chemical, physical, and microbiological stability of 1 mg/ mL CARV– malic acid solution.

15. 3 . DRUG PROFILE Carvedilol: Generic name:- carvedilol Chemical formula: - C 24 H 26 N 2 O 4   Molecular weight: - 513.5 gm/mol. Chemical name: (±)-[3-(9H-carbazol-4-yloxy)-2—hydroxypropyl]-[2-(2methoxyphenoxy)ethyl]amine Category: - Antihypertensive activity. Half life: 7-10 hour Dose: 3.125 to 25 mg. twice a day Description: A white or almost crystalline powder Solubility: sparingly soluble in water and soluble in methanol . Melting point: 114-115 c.  Bioavailability: 25% - 35% Mechanism of Action: Carvedilol is a racemic mixture in which nonselective β- adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency.

16. Metabolism and Excretion: The metabolization of carvedilol is rather significant. Following the oral administration of radiolabeled carvedilol to healthy volunteers, the amount of carvedilol that accounted for the total radioactivity in plasma was only around seven percent, as determined by the area under the curve (AUC). In the urine, less than two percent of the dosage was discharged in its original form. Carvedilol is largely metabolized by the formation of glucuronidation and the oxidation of aromatic rings. A further metabolization of the oxidative metabolites occurs by conjugation, which is accomplished through glucuronidation and sulfation . The metabolites of carvedilol are mostly eliminated from the body through the bile and expelled in the feces. The phenol ring undergoes demethylation and hydroxylation, which results in the production of three active metabolites that possess the ability to inhibit β-receptors. In terms of β-blockage, the 4'-hydroxyphenyl metabolite has been shown to be roughly thirteen times more effective than carvedilol , according to the findings of preclinical research.

17. Pharmacokinetics: Absorption: The oral administration of immediate-release carvedilol tablets results in the quick and wide absorption of carvedilol . The absolute bioavailability of carvedilol is around 25–35 percent, which is attributed to a considerable amount of first-pass metabolism. Extended-release capsules of COREG CR provide about 85 percent of the bioavailability of tablets of carvedilol that are taken immediately after administration. Distribution: Carvedilol is predominantly linked to albumin, which accounts for more than 98% of its binding to plasma proteins. There is no correlation between the concentration of the plasma and the plasma-protein binding over the therapeutic range. Carvedilol is a lipophilic molecule that is basic in nature. It has a steady-state volume of distribution of around 115 L, which indicates that it is distributed into extravascular tissues to a significant degree.

18. Drug-drug interaction:- The following drug interaction studies were performed with immediate-release carvedilol tablets . Amiodarone : Pharmacokinetic research was carried out on 106 Japanese patients who were suffering from heart failure. The study found that the coadministration of modest loading and maintenance doses of amiodarone with carvedilol led to a rise in the steady-state trough concentrations of S(-)- carvedilol that was at least two times higher than the initial concentrations. Cimetidine: The steady-state area under the curve (AUC) of carvedilol was raised by thirty percent when cimetidine (1,000 mg/day) was administered to ten healthy male individuals in a pharmacokinetic trial. However, there was no change in the C max .

19. Digoxin: In 12 hypertensive individuals, the steady-state area under the curve (AUC) and trough concentrations of digoxin rose by 14% and 16%, respectively, after the concurrent treatment of carvedilol (25 mg once daily) and digoxin (0.25 mg once daily) over a period of 14 days. Warfarin: Carvedilol , at a dosage of 12.5 milligrams twice day, did not have any impact on the steady-state prothrombin time ratios, nor did it change the pharmacokinetics of R(+)- and S(-)-warfarin when it was administered concurrently with warfarin in a group of nine healthy volunteers. Indication & Usage: Carvedilol is intended for the treatment of mild to severe heart failure of ischemic or cardiomyopathic origin during congestive heart failure. It is typically used in conjunction with diuretics, ACE inhibitors, and digitalis in order to improve the patient's chances of survival and also to decrease the likelihood of hospitalization (for more information, see clinical trials).

20. Carvedilol is indicated for the treatment of left ventricular dysfunction following myocardial infarction. This medication is prescribed to clinically stable patients who have survived the acute phase of a myocardial infarction and have a left ventricular ejection fraction of forty percent (with or without symptomatic heart failure) (for more information, see clinical trials). Hypertension:  carvedilol is also indicated for the management of essential hypertension. It can be used alone or in combination with other antihypertensive agents, especially thiazide- type.

21. Contraindications/Cautions: hypersensitivity to drug/class/component. bradycardia , severe 2nd or 3rd degree AV block heart failure, uncompensated cardiogenic shock sick sinus syndrome w/o pacemaker asthma, bronchial hepatic diminishing avoid unexpected withdrawal

22. Warning and precaution: The profile of adverse events observed with carvedilol phosphate was generally comparable to that observed with the administration of immediate-release carvedilol in clinical trials of COREG CR in patients with hypertension (338 subjects) and in patients with left ventricular dysfunction following a myocardial infarction or heart failure (187 subjects). These patients were all experiencing heart failure. As a result, the information that is presented in this section is derived from the findings of controlled clinical studies that were conducted using COREG CR and immediate-release carvedilol . As a result, the information that is presented in this section is derived from the findings of controlled clinical trials that were conducted with carvedilol and immediate-release carvedilol . 48

23. 4. AIM AND ODJECTIVES The aim of the thesis project was to optimize the preparation (wet media milling technique) and characterization methods of nanosuspensions for poorly water-soluble drug compounds, then formulate the nanosuspensions into suitable pharmaceutical dosage forms, and finally test the efficacy in in vitro testing. The more specific objectives of the present study are: Optimization of Nanosuspension Preparation Parameters Importance of Particle Size on Dissolution " Nanos -in-Micros" Pharmaceutical Formulation In Vitro Efficacy Testing By studying critical process parameters, assessing the impact of particle size on dissolution behavior, developing innovative pharmaceutical formulations, and conducting in vivo efficacy tests, the project seeks to contribute to the advancement of nanosuspension technology for enhanced drug delivery and therapeutic outcomes.

24. AIM & OBJECTIVE The aim of the research assignment was to enhance the preparation (wet media milling technique) and characterization methods of nanosuspensions for poorly water-soluble drug compounds, subsequently formulate the nanosuspensions into appropriate pharmaceutical dosage forms, and ultimately evaluate the efficacy through in vitro testing. The more specific objectives of the present study are: Importance of Particle Size on Dissolution: The research seeks to examine the relationship between particle size and the dissolving characteristics of nanosuspensions of weakly water-soluble drugs. Both modeling and experimental techniques are utilized to ascertain distinguishing dissolution conditions. This entails assessing the impact of varying particle sizes on the rate and amount of drug dissolution, which is essential for enhancing drug bioavailability.

25. In Vitro Efficacy Testing: The research examines the efficacy of nanocrystal formulations in vitro for medication release. The objective of this work is to employ nanotechnology to develop nanoparticles that improve the solubility of weakly water-soluble drugs, hence enhancing bioavailability. This stage is essential for assessing the practical therapeutic potential of the improved nanosuspension formulations. This thesis topic seeks to enhance the synthesis and characterisation of nanosuspensions for poorly water-soluble pharmaceutical molecules. The project aims to advance nanosuspension technology for improved drug delivery and therapeutic outcomes by examining critical process parameters, evaluating the influence of particle size on dissolution behavior, creating novel pharmaceutical formulations, and performing in vivo efficacy assessments.

26. 1. Literature Review 2. Procurement of drug and excipients 3. Preformulation Studies a) Determination of λmax of the drug b) Calibration curve c) Partition coefficient d) Solubility Studies 4. Formulation development of Nanosuspension. 5. Evaluation of Nanosuspension a) Particles Size b) Size distribution c) Vesicle size determination d) In vitro drug release 6. Stability Studies 5. PLAN OF WORK

27. 6. METHODOLOGY 6.1 Preformulation studies: Preformulation studies can be defined as investigation of physical & chemical properties of drug substance alone and when combined with excipients . Preformulation studies are the first step in rational development of dosage form of a drug substance. The objectives of Preformulation studies are to develop a portfolio of information about the drug substance, so that this information is useful to develop a portfolio of information Preformulation investigations are designed to information is useful to develop formulation. 6.1.1 Solubility Studies: a. Solubility study in water: Drug was added in 100 mg in conical flasks containing 50 ml of distilled water. The flasks were tightly corked and placed in a water bath at 37.0 ± 0.50 C agitated at 100 rpm for at least 12 hrs. Samples were taken at 12 hrs and filtered through 0.45 μm filter, diluted with the medium and the drug concentration in the final sample solutions was determined spectrophotometrically at. Each solubility value was determined in triplicate and the results reported are the mean of the three.

28. b. Solubility study in buffer: Drug was added in 100 mg in six conical flasks each containing pH 1.2 hydrochloric acid, pH 3.0 acid phthalate buffer, pH 4.5 acetate buffer and pH 5.8, 6.8 and 7.2 potassium phosphate buffers were prepared as per IP. The buffers were prepared using distilled water. The solubility of drug in the buffers was measured in the similar manner as in water. 6.1.2 Determination of UV absorption maxima ( ƛmax ) of drug: The stock solution (100µg/ml) of carvedilol was prepared in pH 6.8 phosphate buffer and diluted with 50 ml prepared stock solution. & to obtain concentration of 10 µg/ml. The resultant solution was scanned in the range of 200 – 400 nm on double beam UV spectrophotometer against phosphate buffer as a blank solution. Spectrum was recorded and the suitable absorption maxima were selected at 241 nm.

29. S.No. Active Pharmaceutical Ingredients(API) Source / Manufacture 1 Carvedilol Glenmark Pharma , Mumbai Table 6.1: Active Pharmaceutical Ingredients (API)

30. Chemical / Material Source / Manufacture Ethanol Absolute Changshu Yanguan Chemicals,China Hydroxy propyl Methyl cellulose 15000 cps Central Drug House (P) Ltd. New Delhi, India Lecithin VAV Life Scince Pvt ltd Mumbai India Benzyl Alcohol Thomas baker (chemicals) Pvt. Ltd Mumbai, India Tween 20 Central Drug House Delhi, India Poloxamer Molychem. Pvt. ltd. Mumbai, India PVP Loba Chemical Pvt. Ltd. Mumbai, India DMF Qualigens Fine chemicals Povidone Qualigens Fine chemicals Tween-80 Thomas baker (chemicals)Pvt. Ltd Mumbai,India Hexane Molychem. Pvt. ltd. Mumbai, India Acetone Thomas baker (chemicals)Pvt. Ltd Mumbai,India Table 6.2: Chemical used during the Experimental work

31. Equipment Manufacture Bath sonicator Raj Analytical Services Mohali,India Electronic weighing balance Shimadzu , Japan Eppendorf tubes Tarsons Product Pvt.Ltd.,Kolkata,India Hot air oven Narang Scientific Works New Delhi,India Magnetic stirrer Remi scientific Instruments Mumbai Membrane filters Advanced Micro Devices Ambala cantt,India Microcentrifuge Remi scientific Instruments Mumbai,India Vacuum pump Suguna single phase Chennai,India Micropipette Accupipet Mumbai ,Indaia Particle size Analyzer Malvern Mastersizer Instruments Ltd.,UK pH meter Labindia Ltd.Mumbai,India Prob Sonicator Mesonix,New York,USA UV Spectrophotometer Shimadzu , Japan Vials Tarsons Products Pvt.Ltd.,Kolkata,India Vortex-type mixer Perfit India Tissue Homoginizer Remi scientific Instruments Mumbai,India Table 6.3: Equipment used during the Experimental work

32. 7. RESULTS AND DISCUSSION Angle of repose 39.87 Bulk Density 0.63±0.04 gm/cm 3 Tapped Density 0.77±0.02 gm/cm 3 Compressibility (%) 18.18 % Hausner’s ratio 1.22 7.1 Preformulation studies: 7.1.1 Micromeritical Study: Table 7.1: Micrometrical Study of Carvedilol Drug 7.1.2 Solubility Study: Carvedilol is a whitish powder it was soluble in methanol and Ethyl acetate. Solubility in distilled water and buffer solutions: The solubility of carvedilol in distilled water was found to be 2.60 μg /ml. Solubility at different pH was in following order: pH 3.0 (380 μg /ml )> pH 4.5 (341 μg /ml) > pH 1.2(290 μg /ml) > pH 5.8 (133.11 μg /ml) > pH 6.8 (80.33 μg /ml) > pH 7.2 (72.11 μg /ml).

33. 7.1.3 Appearance: Microparticles were small spherical shape particle, nonporous & uniform mixture. 7.2 Analytical Method development by UV Spectroscopy 7.2.1 Standard curve for Carvedilol It refers to the ability of the analytical procedure to obtain results that are directly proportional to the concentration of analytes at the target level. The linearity for the Carvedilol spectrophotometric analysis was determined by performing a linear regression analysis of the absorbance Carvedilol verses concentration plot (standard curve). The data of the standard curve is described by a linear equation. Y=m x + c

34. Sr. no. Concentration (µgm/ml) Absorbance (nm) 1. 2 0.257 2. 4 0.441 3. 6 0.626 4. 8 0.784 5. 10 0.957 6. 12 1.220 Table 7.2: Data for calibration curve of Carvedilol Figure 7.1: Calibration curve of Carvedilol

35. 7.4.4 Stability of Carvedilol Nanosuspension According to physiochemical analyses, including characteristics such as particle size, PDI, drug content %, and in-vitro release tests, the Carvedilol formulation (F2), made from a mixture of soya lecithin and TPGS, was selected for expedited stability studies. The formulation at room temperature and at 40 °C exhibited a small increase in particle size. The in-vitro dissolution profile data of the nano -formulation indicates that the solubility rates of Carvedilol were adequate in 0.1N HCl . The residual medication content % was exceptional after three months. The aforementioned facts are shown in Table 7.9. Table.7.8: Particle size analysis of selected Carvedilol Nanosuspension (F2) formulation Formulation Storage temperature condition Initial particle size (nm) Particle size after three months (nm)     F2 Room temperature     81.75 ± 92.86 86.63 ± 94.67 40 C 92.13 ± 12.59

36. Summary and Conclusion SUMMARY: To produce the Nanosuspension formulation of Carvedilol , the preformulation studies conducted for Carvedilol revealed key micromeritic properties indicative of its flow characteristics and powder behavior. The angle of repose was found to be 39.87°, suggesting fair to passable flow properties. The bulk density and tapped density were recorded as 0.63 ± 0.04 g/cm³ and 0.77 ± 0.02 g/cm³, respectively. These values indicate a moderate packing ability of the powder. The compressibility index (Carr’s index) was calculated to be 18.18%, and the Hausner’s ratio was 1.22, both of which further suggest fair flow properties. These results provide a foundational understanding of Carvedilol’s physical characteristics, which are essential for the development of a suitable and efficient drug delivery system. Carvedilol shows significantly higher solubility in organic solvents compared to water. It is most soluble in DMF (131.41 ± 1.45 mg/mL) and benzyl alcohol (110.01 ± 1.64 mg/mL), followed by ethanol (23.76 ± 1.45 mg/mL) and acetone (7.57 ± 0.54 mg/mL). In contrast, its solubility in water is extremely low (0.03 ± 0.91 mg/mL), indicating poor aqueous solubility and a strong preference for lipophilic environments.

37. CONCLUSION In conclusion, Carvedilol nanosuspension formulations required extensive characterization and optimization. Initial purity investigations showed Carvedilol met pharmacopoeia criteria, allowing for further development. Carvedilol's 241 nm absorption maxima confirmed its structure using UV spectroscopy. According to Beer-Lambert's law, calibration curves showed a linear connection between Carvedilol concentration and UV absorbance. Stabilizers were examined for particle size and dispersion to make nanosuspensions using high-pressure homogenization. The nanosuspensions had homogeneous particle sizes and limited size distributions, indicating stability and drug delivery capability.  

38. Formulation F2 was the optimal nanosuspension , with high drug content, entrapment effectiveness, and simulated stomach fluid solubility. In-vitro dissolution tests revealed zero-order F2 release kinetics, emphasizing continuous and controlled drug release over 12 hours. Stability experiments showed that the optimized formulation did not alter in physical appearance or medication content after 90 days under accelerated settings. These findings suggest that Carvedilol nanosuspensions may increase therapeutic efficacy by improving stability, solubility, and controlled release. The successful creation of Carvedilol nanosuspension formulation may improve medication solubility, bioavailability, and therapeutic efficacy, enabling better treatment alternatives for numerous medical problems.

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