Development of Posaconazole delayed-release tablets by high shear melt Granulation Technique

 

Ketan B. Ramani1*, Dr. Vipul Patel2

1Research Scholar, School of Pharmacy, RK University, Rajkot, Gujarat, India.

2Associate Professor, School of Pharmacy, RK University, Rajkot, Gujarat, India.

*Corresponding Author E-mail: ketanbramani@gmail.com

 

ABSTRACT:

Pharmaceutical industries, particularly small and medium scale enterprises (SMEs) always prefer a manufacturing process that involves conventional equipment and devoid of solvents due to commercial, safety and ecological reasons. However, some drug products like Posaconazole delayed-release tablets are currently manufactured by the processes that require complex/ costly equipment or a huge quantity of solvent and specifically skilled personnel. Aim of this study was to simplify delayed-release dosage form of Posaconazole, a BCS class IV drug having pH dependent solubility by the simple yet innovative manufacturing process. The study employed high shear melt granulation (HSMG) technique for manufacturing of drug product. Drug release controlling excipients namely Eudragit L100, triethylcitrate and Macrogol 6000 were selected, as these are suitable excipients for solventless processing at high temperature. Levels of drug release controlling ingredients were optimized using one factor at a time (OFAT) approach. Itwas revealed that drug release from the formulation was affected by the level of Eudragit L100, and Eudragit L100: Macrogol 6000 ratio. The optimized formulation was found satisfactory and reproducible with respect to all the studied pharmacotechnical parameters. The product was found stable at the accelerated storage conditions. In conclusion, Posaconazole delayed-release tablets can be prepared by conventional set of equipment, which are available at most of the pharmaceutical SME by using the explored HSMG technique.

 

KEYWORDS: Posaconazole, melt granulation, high shear, solventless, delayed-release, solid dispersion.

 

 


INTRODUCTION:

Notwithstanding advancement in processing techniques to prepare solid dispersion of drug in carrier polymer, small and medium scale pharmaceutical industries (SMPI) vacillating to manufacture such drug products due to higher technological investment to prepare such dosage forms. Hence, there is a craving need to explore a cost effective processing technique which does not involve any specialized equipment.

 

Posaconazole delayed-release tablets is such a dosage form where in the drug product is molecularly dispersed in enteric polymer. Posaconazole is a newer anti-fungal drug, which used to treat life-threatening conditions caused by fungal infection.1,2 It is a BCS class IV drug, which is having good solubility in acidic media, but having poor solubility in basic media. So, as described in patent application no. WO 2009/129300 A2, orally administered Posaconazole dissolves in stomach fluids and when this stomach fluid reaches the environment of the intestine (typically less acidic than about pH 6.4) a substantial amount of the dissolved posaconazole precipitates, hindering absorption in the intestine. It has been determined that in environments where the pH is about pH 6.4 or more basic, the solubility of posaconazole free base is less than about 1µg/mL.3 Hence, in commercially available solid oral formulations, Posaconazole is formulated as solid suspension or solid solution in enteric coating polymers to enhance the solubility in alkaline pH and to protect the drug from acidic environment of stomach where it has higher solubility.3–7 The formulations mentioned in prior the art were processed by hot melt extrusion process. Some other prior arts also mentioned spray drying, freeze drying and wet granulation by top spray method. All of these techniques requires specific, expensive equipment and huge quantity of solvent(s). So, it becomes difficult for SMPI to manufacture such type of product.

 

Prior art:

Patent# WO2009129300 discloses compositions wherein Posaconazole is molecularly dispersed in hydroxy propyl methyl cellulose-derivative polymer by using hot melt extrusion. This patent states that Pharmacokinetic parameters of Posaconazole can be improved by preparing solid dispersion of the drug in enteric polymers such as HPMC-AS. The patent discloses drug: Polymer ration and a temperature range for hot melt extrusion process.3

 

Patent application# US20150231081 discloses the use of polymer other than HPMC derived polymer to prepare hot melt extrudes of Posaconazole solid dispersion. Here, the embodiments disclose use of methacrylic acid and ethyl acrylate polymer (Eudragit L 100-55) to prepare drug polymer extrudates.5

 

Patent# WO2017/032908A1 discloses the method of preparation of posaconazole formulation by top spray granulation method wherein posaconazole is dissolved in a common solvent with HPMCAS and Methacrylic acid – methyl methacrylate copolymer (1:1). The solution is sprayed over microcrystalline cellulose. Many prior arts also described in the patent wherein hot melt extrusion, freeze drying and spray drying processes are disclosed. However, these techniques require specific and expensive equipment which are not present in most of the pharmaceutical production plants.6

 

Patent application# EP3210599 A1 discloses the use of water soluble, neutral or anionic polysaccharide as precipitation inhibitor in solid solution of posaconazole in enteric polymer. Additionally, it also states that the process of melt extrusion should be carried out in temperature below 160°C because, beyond this temperature, posaconazole is degraded. Hence, as per the disclosure, the processing temperature can be lowered by using a non-enteric polymer other than a neutral or anionic polysaccharide. The patent also states that the presence of a sugar alcohol in the mixture that is subjected to hot-melt extrusion may increase the chemical stability of posaconazole.8

 

Patent# WO2015154718 discloses the composition of posaconazole and vinyl pyrrolidone-vinyl acetate copolymer or a polymer containing ethylene glycol units. Here also, it is noted that an enteric polymer must require to prepare solid dispersion. The solid dispersions are prepared by the process of hot melt extrusion.9

 

Kathuria A, found that Eudragit L100 and Eudragit S 100 polymers can be used for dry coating process. Here, they used Vector GXR-35 Rotary Granulator/Coater, which is again a complex equipment. However, it was revealed that polymer : plasticizer ratio 2:1 was required to produce the film using dry coating technique.10

 

Introduction to High shear melt granulation technique:

Melt granulation is a process by which pharmaceutical powders are efficiently agglomerated by use of a binder which melts during the process. This concept was reported in some research works in late 1970 and early 1980, but after that it is seems that it was not studied widely.11,12 High shear melt granulation (HSMG) technique has been explored for its applicability like solubility enhancement and controlling the drug release. Some work regarding taste masking and compressibility improvement has also been reported.13

 

 

Figure 1 General processing flow of a high shear melt granulation process12

 

Following are some explored application of melt granulation techniques:

A sustained release matrix formulation of Verapamil HCl, a BCS class I drug was prepared using melt granulation technique. The matrix was prepared by waxes namely Glyceryl monostearate and stearic acid and combination thereof. The study revealed that the combination of the waxes was more drug release retarding than alone waxes. Further, it was also observed that drug release was decreased with increase in the level of waxes.14 Similar way, a sustain release wax matrix tablet formulation of Metoprolol succinate was prepared. Here, hydrogenated vegetable oil, Compritol and Precirol were evaluated as release retarding ingredients. It was observed that release retardant effect was found in order of hydrogenated vegetable oil > Compritol > Precirol.15 Solubility of Telmisartan was successfully improved by preparing its solid dispersion with alkalized using polyethylene glycol (PEG) as carrier. The solid dispersion was prepared using hot melt method wherein drug, alkalizer, and PEG mixture was heated at 100°C with constant stirring. It was concluded that solid dispersion containing alkalizer may improve the dissolution of pH dependent drug like telmisartan.16

 

Solid dispersion of poorly soluble drugs in hydrophilic polymers is a well-explored technique to improve aqueous solubility of poorly soluble drug. Solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic inert carrier or matrix and a hydrophobic drug. Primarily, solid dispersion improves solubility by exposing molecularly dispersed colloidal particles of drug substances to aqueous media which dissolves at a faster rate due to manifold increase in surface area. Carriers which are explored by researchers includes hydrophilic polymers like polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose; pH dependant polymers like hydroxypropyl methyl cellulose phthalate and Eudragit; and some non polymeric materials like Urea, mannitol, gums.17–21 Various types of solid dispersion and methods to prepare such solid dispersions are well explored by researchers. Melt granulation is one of the newer techniques to prepare solid dispersion wherein the solid dispersion can be prepared in a conventional high shear mixer. In this technique, binder which acts as carrier also, is heated with drug and other ingredients above its melting point to form solid dispersion. This process is more preferable due to its better process controls.22 A solid dispersion of Aceclofenac was prepared using hot melt technique to enhance solubility of the drug. In this study, a mixture of drug and PVP K-30 was heated at 70°C to form molten mass. The optimized formulation demonstrated increased solubility of the drug substance.23 A solid dispersion of nifedipine which was used as model drug was evaluated. In this study, solubility of nifedipine was successfully improved by preparing its solid dispersion in matrix of hydroxy propyl methyl cellulose K-4M and Eudragit RS-100. The solid dispersion was prepared by melt fusion technique wherein methanol was used as solvent.24

 

Looking at the craving demand of SMPI, an attempt has been made to demonstrate that Posaconazole delayed-release tablets can be prepared using conventional equipment and cost effectively by unique melt-granulation technique. Here, the excipients were selected based on literature study which includes various patents, peer reviewed articles, leaflet and approval package of marketed product, and excipient manufacturer’s recommendations. Level of release controlling components viz. Drug: Enteric polymer and Enteric polymer: meltable binder cum hydrophilic polymer were optimized by one factor at a time (OFAT) approach. The targets were to achieve delayed drug release profile and the optimized product should be stable at accelerated condition (40°C/ 75%RH) for six months.

 

MATERIALS AND METHODS:

Materials:

Posaconazole amorphous was received as a gift sample from Amneal (Ahmedabad, India) and all other excipients namely Eudragit L100 (Evonik), tri-ethylcitrate (Vertellus), Polyethylene glycol 6000 (Clariant), Microcrystalline cellulose – Avicel PH 102 (FMC), Methocel E5 (Colorcon India), Cros-carmellose sodium (FMC), Aerosil (Evonik) and Magnesium stearate (Peter Greven) were received from Piramal Pharmaceutical developments services (Ahmedabad, India). All other reagent used were of analytical grade.

 

Preparation of solid dispersion:

Composition of the solid dispersion was optimized. Ratio of the drug release controlling components viz. Posaconazole: Eudragit L100 and Eudragit L100: PEG 6000, were optimized using one factor at a time (OFAT) approach. Level of Triethylcitrate (TEC) was fixed at 50% of Eudragit base on cited literature.10 Formulae of Posaconazole: Eudragit L100 and Eudragit L100: PEG 6000 ratio optimization trials are tabulated in Table 1 and Table 2 respectively. The trial batches were manufactured using melt granulation technique as mentioned in Figure 2.


 

Table 1 Formulae of Posaconazole: Eudragit L100 ratio optimization trials

Batch#

P2

P3

P4

Batch Detail

Posaconazole: Eudragit L100 ratio

1 : 1

1 : 1.5

1 : 2

Ingredient

g/ batch

% w/w

g/ batch

% w/w

g/ batch

% w/w

Posaconazole (amorphous)

100

26.67

100

21.62

100

18.18

Eudragit L100

100

26.67

150

32.43

200

36.36

Triethylcitrate (TEC)

50

13.33

75

16.22

100

18.18

Polyethylene glycol 6000 (PEG 6000)

25

6.67

37.5

8.11

50

9.09

Microcrystalline cellulose (AVICEL PH 102)

100

26.67

100

21.62

100

18.18

Total

375

100.00

462.5

100.00

550

100.00

 

Table 2 Formulae of Eudragit L100: PEG 6000 ratio optimization trials

Batch#

P5

P3

P6

P7

Batch Detail

Eudragit L100 : PEG 6000 ratio

1 : 1.5

1 : 0.15

1 : 0.35

1 : 0.45

Ingredient

g/ batch

% w/w

g/ batch

% w/w

g/ batch

% w/w

g/ batch

% w/w

Posaconazole (amorphous)

100.0

22.35

100

21.62

100.0

20.94

100.0

20.30

Eudragit L100

150.0

33.52

150

32.43

150.0

31.41

150.0

30.46

Triethylcitrate (TEC)

75.0

16.76

75

16.22

75.0

15.71

75.0

15.23

Polyethylene glycol 6000 (PEG 6000)

22.5

5.03

37.5

8.11

52.5

10.99

67.5

13.71

Microcrystalline cellulose (AVICEL PH 102)

100.0

22.35

100.0

21.62

100.0

20.94

100.0

20.30

Total

447.5

100.00

462.5

100.00

477.5

100.00

492.5

100.00

 

 

Figure 2 High Shear melt granulation process for manufacturing of Solid dispersion

 

Table 3 Formula of Posaconazole delayed-release tablets 100 mg

Batch# P8

Sr. No.

Ingredients

Qty/tablet (mg)

%w/w

Solid dispersion

1

Posaconazole (amorphous)

100.0

14.29

2

Eudragit L 100

150.0

21.43

3

Triethylcitrate

75.0

10.71

4

Polyethylene glycol

52.5

7.50

5

Microcrystalline cellulose (AVICEL PH 102)

100.0

14.29

Extra-granular

6

Microcrystalline cellulose (AVICEL PH 102)

159.5

22.79

7

Hypromellose (Methocel E5)

35.0

5.00

8

Croscarmellose sodium

14.0

2.00

9

Colloidal silicon dioxide (Aerosil 200 Pharma)

7.0

1.00

Lubricant

10

Magnesium stearate

7.0

1.00

Core Total

700.0

100.00

Film-coating (3% w/w weight gainof core tablets)

11

Opadry® II Yellow

21.0

3% of core

12

Purified water

q.s.

--

Total

721.0

--

 


Preparation of tablet:

The optimized solid dispersion was compressed in to tablets using commonly used excipients. The tablets were then film-coated by spraying aqueous dispersion of a ready-mix coating material over the rolling bed of compressed tablets in auto-coater. Formula of the film-coated tablets is tabulated in Table 3.

 

Assay:25

Standard preparation:

Posaconazole reference standard was accurately weighed and dissolved in methanol to yield concentration of 25.0 µg/mL, this was diluted to 10.0 µg/mL using same solvent.

 

Sample preparation:

Ten tablets were crushed using mortar-pastel. The 50 mg equivalent crushed powder was weighed and dispersed in 50 mL Acetone with continuous stirring for 30 minutes and then centrifuged for 5 minutes. The supernatant was diluted with methanol to prepare 10 μg/mL solution.

 

Standard and samples were analyzed in a double beam UV-spectrophotometer at wavelength of 260nm.

 

Dissolution method:26

Dissolution method for Posaconazole method was used as recommended by office of generic drugs, US-FDA. Following is the dissolution method for Posaconazole DR Tablets:

Apparatus: USP II (Paddle), 75 rpm

Media:

Acid Stage: 0.01 N HCl, 750 mL

Buffer Stage: 50 mM phosphate buffer, pH 6.8 with 0.37 % Polysorbate 80 (after 120 minutes, to the acid stage, add 250 mL of 0.2M Phosphate Buffer, 1.46% Polysorbate 80), 1000 mL

 

Media:

Acid Stage: 0.01 N HCl, 750 mL

Buffer Stage: 50mM phosphate buffer, pH 6.8 with 0.37 % Polysorbate 80 (after 120 minutes, to the acid stage, add 250 mL of 0.2M Phosphate Buffer, 1.46% Polysorbate 80), 1000 mL

 

Aliquots measuring 10mL were withdrawn at each time-point, filtered through 0.45µ Millipore membrane filter and analyzed by UV-spectrophotometer after appropriate dilution to yield the sample solution having concentration in a range of 5.0µg/mL to 25.0µg/mL.

 

Stability study:

The optimized batch (Batch# P8) was packed in 40 CC, Round, HDPE bottle with child resistant cap. Thirty tablets were packed in each bottles and the packed tablets were kept on stability in accelerated condition (40°C±2°C/75% RH ± 5%) for 6 months.

 

Alcohol dose dumping study:

Co-administration of alcoholic beverages may affect drug release form a modified release solid oral dosage form leading to rapid dumping of complete or fraction dose. Dose-dumping can pose a significant risk to patients, either due to safety issues or diminished efficacy or both. Generally dose-dumping is observed due to a compromise of the release-rate-controlling mechanism. Hence, regulatory agencies are recommending that in-vitro dissolution studies should be conducted to determine the potential for dose dumping. So, a dissolution study was carried out on the optimized batch (Batch# P8) as per US-FDA recommendation.27, 28

RESULTS AND DISCUSSION:

Optimization of Posaconazole: Eudragit L 100 ratio

Dissolution profiles of Posaconazole: Eudragit L 100 ratio optimization trials are graphically represented in Figure 3. Here, it can be observed that in batch# P2, the drug was released more than 10% in acidic media, which means that enteric protection is not appropriate. Further, in this batch, drug was not dissolved completely in buffer stage. So, here, the level of Eudragit L100 is not appropriate. In batch# P3 and P4, the drug release was satisfactory in acid and buffer stage. However, in batch P4, the drug release profile was slower when compared to batch# P3. Hence, 1: 1.5 proportion of Posaconazole: Eudragit L 100 was selected.

 

Figure 3 Comparative dissolution profiles of Posaconazole : Eudragit L 100 ratio optimization trials

 

Optimization of Eudragit L100: PEG 6000 ratio:

In batch# P5, the impeller of RMG was overload and jammed. This means that more PEG is required for better processibility when material is in the molten state. Batch# P3 and P6 shown satisfactory drug release profiles in acid and buffer stage dissolution as observed in Figure 4. However, the drug was completely (more than 85%) dissolved within 15 minutes in batch# P6. Further, in batch# P7, more than 10% drug was dissolved in the acid stage which may be due to more amount of PEG. Hence, 1 : 0.35 proportion of Eudragit L100 : PEG 6000 was selected.

 

 

Figure 4 Comparative dissolution profiles of Eudragit L100 : PEG 6000 ratio optimization trials

Physical characterization data of Posaconazole DR tablets 100mg:

The optimized batch P6 was reproduced as batch# P8 and solid dispersion of this batch was evaluated for compression process as per formula given in Table 3. Physico-chemical characterization data of tablets are given in Table-4. The dissolution profile of solid dispersion and tablets are given in Figure 5. Physico-chemical characterization data and dissolution profile of Posaconazole delayed-release tablets 100 mg were found satisfactory. Dissolution profile of batch# P6 and P8 were found comparable, which means that the formula and process for preparation of Posaconazole-Eudragit L100 solid dispersion are reproducible. Drug release profiles of solid dispersion and tablets are comparable which revealed that compression of solid dispersion in tablets does not have any impact on the drug release profile.

 

Table 4 Physical characterization data of Posaconazole DR tablets 100 mg: Optimized batch (Batch# P8)

Weight (N=20) (mg) (Individual Minitablets)

Target: 7 mg ± 1 mg

Average

701.30

Minimum

694

Maximum

711

Thickness (N=20) (mm)

Average

6.08

Minimum

6.00

Maximum

6.13

Hardness (N=20) (N)

Target: 25N ± 5 N (for average)

Average

204.0

Minimum

179

Maximum

223

Friability (%)

Target: NMT 1.0%

0.17

Disintegration time (N=6) (min’Sec”)

1’24”

Assay (Target: 90.0% to 110.0%)

97.9

Loss on drying

2.24

 

 

Figure 5 Comparative dissolution profiles: Solid dispersion of Batch# P6, solid dispersion of batch# P8 and tablets of batch# P8

 

Stability study:

Stability study data of the optimized formulation (Batch# P8) is summarized in Table 5. There was no significant change observed in tablet hardness and assay after 6 month storage at accelerated condition compared to their initial values. Further, dissolution profiles at initial and after 6 months at accelerated condition were also comparable. So, it can be concluded that the drug product is stable.


 

Table 5 Stability study data Posaconazole delayed-release tablets 100 mg

Batch# P8

Pack style: 40CC, Round, HDPE bottle with CR cap, 30 counts

Stability condition: 40°C ± 2°C/75% RH ± 5%

Test

Specification

Initial

Accelerated condition, 6 months

Tablet Hardness (avg)

-NA-

204 N

198 N

Assay

90.0% - 110.0%

97.9%

98.1%

Dissolution Conditions (N=6):

Specification:

Acid stage: NMT 10% at 120 min, Buffer stage: NMT 75% (Q) drug release in 30 min

 


 

Alcohol Dose dumping study:

Comparative dissolution profiles of Posaconazole from the delayed-release tablets in dissolution media with 0% v/v and 40% v/v alcohol are given in below Table 6. The data revealed that the drug was not dissolved more than 10% when studies without alcohol and with 40% v/v alcohol. This reveals that dose is not dumping from the dosage form in alcohol induced dose dumping study.

 

Table 6 Comparative dissolution profiles: Alcohol dose dumping study

Batch#

P8

P8

Alcohol concentration in dissolution media

0% v/v

40%v/v

Time (minutes)

% Drug Released

min - max

% Drug Released

min - max

30

1

0 – 2

1

0 – 2

60

1

0 – 2

1

0 – 3

90

2

1 – 4

6

4 – 8

120

5

4 – 7

8

6 – 10

Dissolution Conditions (N=6):

Apparatus: USP II (Paddle), 75 rpm

Media: 0.01 N HCl, 750 mL with or without alcohol

 

CONCLUSION:

From the dissolution profiles and other pharmaco- technical parameters of the optimized trial, it can be concluded that the drug product, Posaconazole Delayed-release Tablets was successfully developed. The optimized formulation was reproducible, stable and was satisfactory with respect to alcohol induced dose dumping study. It can also be concluded that Posaconazole delayed-release tablets can be prepared by melt granulation technique using conventional equipment. The explored melt granulation process was found capable to replace the existing complex process which required costly and complex equipments.

 

REFERENCES:

1.      Dave R, Vyasa B, Daniel P, Anand I, Patel C. A Review on Posaconazole: A Newer Antifungal. Research J Pharm and Tech. 2010;3(3):694-699.

2.      USFDA Label of Noxafil (Posaconazole). https://www.accessdata. fda.gov/drugsatfda_docs/label/2015/022003s018s020,0205053s002s004,0205596s001s003lbl.pdf.

3.      Fang LY, Harris D, Krishna G, et al. High-density compositions containing posaconazole and formulations comprising the same. https://patents.google.com/patent/WO2009129300A2/en. Accessed January 18, 2020.

4.      Sharpe S, Sequeira J, Harris D, Mahashabde S. Antifungal composition with enhanced boavailability. March 2003. https://patents. google.com/patent/US20030055067. Accessed January 18, 2019.

5.      Kulkarni SK, Mehta PR, Kapoor R, Maheshwari RKB. Delayed-release posaconazole tablets. :5. https://patents.google.com/patent/ US20150231081A1/en?oq=US20150231081A1. Accessed January 18, 2019.

6.      Guillan MG, Nieto LN, Fernandez LA, Calzada JV. Pharmaceutical composition comprising amorphous posaconazole. https://patents.google.com/patent/WO2017032908A1/en?oq=WO2017032908A1. Accessed January 18, 2019.

7.      Wan J, Sheng X. Posaconazole pharmaceutical compositions and preparation methods, uses and pharmaceutical formulations thereof. July 2018. https://patents.google.com/patent/US10022373B2/en.

8.      Prathap VR, Kalamata VN, Rallabandi BRC, Hendrik S, Ansgar F. Gastro-resistant formulation containing posaconazole and a polymeric precipitation inhibitor. August 2017. https://patents.google.com/patent/ EP3210599A1/en?oq=EP3210599A1

9.      Jiansheng W, Kun L, Xiaoqian S. Posaconazole pharmaceutical composition and preparation method, application and pharmaceutical preparation thereof. October 2015. https://patents.google.com/patent/ WO2015154718A1/en. Accessed February 21, 2020.

10.   Kathuria A, Asgarzadeh F, Engels S, Jensen B. Enteric Protection for Multi-particulates Using Eudragit® L 100 and Eudragit® S 100 Polymers in a Novel Rotor Granulation Dry Coating Process. In: Poster #R6141. AAPS Annual Meeting & Exposition; 2011.

11.   Wong T, Cheong W, Hang P. Melt Granulation and Pelletization. In: Handbook of Pharmaceutical Granulation Technology - Edited by Dilip M. Parikh. 2nd ed. USA: Taylor & Francis Group; 2005:385-406.

12.   Shanmugam S. Granulation techniques and technologies: recent progresses. Bioimpacts. 2017;5(1):55-63. doi:10.15171/bi.2015.04

13.   Desai U, Chaudhari P, Bhavsar D, Chavan R. Melt granulation: An alternative to traditional granulation techniques. Indian Drugs. 2013; 50: 5-13.

14.   Bhagwat DA, Kawtikwar PS, Sakarkar DM. Sustained release matrices of Verapamil HCl using glyceryl monosterate and stearic acid. Research J Pharm and Tech. 2008;1(4):405-409.

15.   Mahaparale PR, Kuchekar BS. Sustained release wax matrix tablet of Metoprolol succinate. Research J Pharm and Tech. 2012;5(11):1408-1412.

16.   Patil M, Keny R, Pimprikar R, et al. Physicochemical Characterization of Solid Dispersion of Telmisartan with Alkaliser by Hot Melt Method. Research Journal of Pharmaceutical Dosage Forms and Technology. 2009;1(3):250-253.

17.   Punitha S, Srinivasa Reddy G, Srikrishna T, Lakshman Kumar M. Solid Dispersions: A Review. Research Journal of Pharmacy and Technology. 2011;4(3):331-334.

18.   Chitlange SS, Pawbake GR, S.V. Pandkar, S.B. Wankhede. Formulation and Evaluation of Diacerein Solid Dispersion for Solubility and Dissolution Rate Enhancement. Research Journal of Pharmacy and Technology. 2011;4(6):932-937.

19.   Pradeep NS. A Review: Increasing Solubility of Poorly Soluble Drugs, by Solid Dispersion Technique. Research Journal of Pharmacy and Technology. 2011;4(12):1933-1940.

20.   Jadhav YL, Parashar B, Ostwal PP, Jain MS. Solid Dispersion: Solubility Enhancement for Poorly Water-Soluble Drug. Research Journal of Pharmacy and Technology. 2012;5(2):190-197.

21.   Bhore SD. A Review on Solid Dispersion as a Technique for Enhancement of Bioavailability of Poorly Water-Soluble Drugs. Research Journal of Pharmacy and Technology. 2014;7(12):1485-1491.

22.   Wagh MP, Bele MH, Patel JS, Pawar AY. Alternative Strategies in Solid Dispersion Manufacturing. Research Journal of Pharmaceutical Dosage Forms and Technology. 2010;2(1):14-22.

23.   Shaikh MV, Thube R. Solubility enhancement of Aceclofenac by hot melt solid dispersion technique. Research J Pharm and Tech. 2011; 4(8): 1307-1310.

24.   Hajare A, Shetty Y, Mali M, Sarvagod S. Characterization of Melt (Fusion) Solid Dispersions of Nifedipine. Research Journal of Pharmacy and Technology. 2008;1(3):230-234.

25.   Bitencourt AS, Oliveira SS, Mendez ASL, Garcia CV. UV Spectrophotometric method for determination of posaconazole: Comparison to HPLC. Journal of Basic and Applied Pharmaceutical Sciences. 2015;36(4):491-495.

26.   Dissolution Methods. https://www.accessdata.fda.gov/scripts/CDER/ dissolution/dsp_SearchResults.cfm. Accessed February 22, 2020.

27.   Bioavailability studies submitted in NDA or INDs - General considerations: Appendix C: Guidelines for conducting in-vitro alcohol dose-dumping study. https://www.fda.gov/media/121311/download. Accessed February 9, 2020.

28.   Friebe TP, Asgarzadeh F, Gray A, et al. Regulatory Considerations for Alcohol-Induced Dose Dumping of Oral Modified-Release Formulations. Pharmaceutical Technology. 2015;38(10):40-46.

 

 

 

 

Received on 25.02.2020           Modified on 21.05.2020

Accepted on 28.07.2020         © RJPT All right reserved

Research J. Pharm. and Tech. 2021; 14(1):96-102.

DOI: 10.5958/0974-360X.2021.00018.4