Preparation, Characterization and Optimization of Maltodextrin based Efavirenz loaded Proniosomes using Box Behnken Design:

In vitro and ex-vivo permeation study


Swarupa Arvapalli1*, A. Anka Rao2

1Research Scholar, College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram,

Andhra Pradesh. 522502.

2Associate Professor, College of Pharmacy, Koneru Lakshmaiah Education Foundation, Vaddeswaram,

Andhra Pradesh. 522502.

*Corresponding Author E-mail:



This research work focuses on development of proniosomal efavirenz (EFV) formulation using maltodextrin as a carrier. Thus an effort is made to increase the effectiveness of oral drug delivery of EFV by blending them in proniosomal powders (maltodextrin-based). The slurry method was employed for the preparation of proniosomes. A mix of Span-60, cholesterol and maltodextrin were used for its preparation..Box Behnken Design used  to study the effect of  independent  variables X1, X2, and X3 (maltodextrin, Span-60 and cholesterol)  on response variables Y1, Y2 and Y3 (Entrapment efficiency ,Vesicle size  and Cumulative Drug Release percentage). Scanning Optical electron microscopy was used for studying surface-morphology of proniosome (optimized) and proniosome formation. To study any drug interaction or its conversion to the molecular and amorphous state from crystalline state, various tests like  differential scanning calorimetry and FT-IR   were  performed. Compared to EFV in pure form, the proniosomalmaltodextrinbaseddrug showed better dissolution 98.41% in vitro-dissolution study. The  optimized Efavirenz loaded proniosomal formulation showed maximum permeation (2614±215µg) in rat intestine as compared to pure drug(1500±114µg). The effectiveness of this drug (oral delivery) is obvious from the fact that rat intestine drug permeation is better. This shows maltodextrin-based EVF proniosomal formulation is  suitable for oral  delivery of efavirenz.


KEYWORDS: Maltodextrin, Intestinal-Permeation, Slurry-method, Proniosome, Efavirenz, Box-Behnken design.




The problem of bioavailability of the administered drug is one of the major issues when it comes to oral delivery, which arises due to lack of dose proportionality, intra and inter-subject variability, unpredictable absorption, and weak dissolution1. Even if the oral route of drug administration is preferred mostly, this problem is existent for most existent and newly discovered drugs.


To address the problem of low solubility of class-II drugs (according to B.C.S classification) proniosomal method is used in this research which can enhance the rate of dissolution2,3 Microencapsulation, spray drying, surface area enhancement through nanonization/ micronization, surfactant inclusion, solid dispersion, drug derivatization, and complexation are various methods for increasing the rate of dissolution of insoluble drugs4 Apart from this, storage  and sterilization of such drugs is difficult in the original  form. Since proniosomes  are powder formulations, dry in nature and contain carrier particles which are coated with  surfactant  and water soluble, they can easily dissolve in agitated aqueous  media to form  niosomal dispersion (niosomes formed are more uniform in size compared to standard niosomes)5-7. They are also easy to store and sterilize because of its free flowing powdery formulation which adds to the convenience of measurement,  transfer, storage and distribution8 traditionally is administered  in high doses due to its low bioavailability (40-45%) which comes because  of its high plasma-protein binding (more than 99%)9 Since the drug non-nucleoside reverse-transcriptase inhibitor and is highly lipophilic,10 it's generally  used in first-line paediatric therapeutic-cocktail (dosage range: 200-600/ day)11. However, its lipophilic nature (log P = 5.4)) and low water solubility (8.3μg/ml) limits absorption when administered through the oral route. Thus, there is a need to enhance bioavailability and dissolution characteristics of EFV.  While EFV has been previously formulated as nanoparticles and solid dispersible particles for addressing these issues, there were no studies of formulation of EFV using maltodextrin  basedproniosomal powders which can  be administered orally. Thus, this paper encompasses a systematic study of formulation of proniosomal powders with EFV ( Maltodextrin based). Further in the study, rat intestine has been experimented (ex- vivo) to assess the  permeability  of EFV from its proniosomal formulation.




The drugs used  for the study were sourced from various chemical laboratories and industries in India and abroad. Maltodextrin: Hi-Media, Mumbai, India. Cholesterol: E. Merck, Mumbai, India.Span -60 ( Sorbitan monostearate )and Cholesterol:Sigma Chemical Co., St. Louis, MO, USA. EFA was received as a present from  Dr. Reddy’s laboratories, Hyderabad, India. Double-distilled water (Freshly collected) was used  for all the experiments. HPLC grade solvents were used and chemicals were of analytical grade.


Box-Behnken Experimental Design:

Optimized proniosomal EFV  can be formulated using BBD   For the predicted outcome, the effect of  three factors (independent  variables) namely X2, X3, and X1(Span-60, cholesterol and maltodextrin ) with three levels (0, 1 and−1 ) were observed by varying the quantities to record effect on different response variables namely Y2, Y3 and Y1(Vesicle size, Cumulative Drug Release percentage,  and Entrapment efficiency). The multidimensional  cube can be considered  as a response surface which has a set of points in each side (middle) and similar 3 centre points. BBD is a suitable  tool to construct second-order polynomial equations and reach out quadratic response surfaces more efficiently. Thus, after tabulating the independent and dependent variables 12 (Table No-1), the polynomial equation can be derived.  This derivation was conducted using the 12th version of the Design-Expert software program (Stat-Ease Inc., Minneapolis, MN).

Yi= b0 + b 1X1+ b 2 X2+ b 3 X 3+ b12 X1X2+ b 13X1X3+ b 23X 2 X 3+ b1 X12 +b 2 X22  +b 3 X32


X1, X2, and X3 are the independent variables, b1 to b3 are regression coefficients, b0 is the intercept and Yi is the dependent variable;


Table No 1: Factors and their levels in Box-Behnken Design




Low (-1)

Mid (0)

High (+1)

X1= Maltodextrin (mg)














Y1=Entrapment Efficiency%

Y2=Vesicle Diameter nm

Y3=% Drug Released %





Formulation  ofproniosomes:

Proniosome was prepared by slurry method after some preliminary trials13. The process starts with dissolving specific quantities of cholesterol, span-60, and maltodextrin in 1:1 ratio with 10ml of methanol and chloroform. To achieve  the desired dissolved solution, heating is necessary to 45 degrees Celsius with sonification. Then, mannitol powder as a carrier is added to a flask (250ml, round bottom) in which the solution is blended. The amount of solvent varies if a more surfactant-based formulation is required. Now, the slurry inside the flask is kept at low pressure and a temperature of 49±2°C for evaporating using a rotary evaporator (speed: 60 RPM, MAKE: Rotavap Hedlop-600, Switzerland). After 15 minutes, a thin layer of maltodextrin powder is obtained, which is kept safely in airtight containers for further processing and estimation. The formulae used are demonstrated in Table 2 (in accordance to B.B.D. method).


Preparation of niosomes from proniosomes:

Niosomal suspension was formed from proniosomal powder (for each formula) after blending with 800C hot distilled water. This niosomes estimation is essential for finding the vesicle size and EE. A vortex-mixer was used for blending the whole solution for 2 mins, and a sonicator was used for sonicating again for 30 seconds. The sonicator and vortex mixer used were of Raypa, UCD-200 and Stuart, USA respectively.


Characterization of the prepared proniosomes:

Determination of entrapment efficiency (EE%):

The nano- vesicles contain EFV in the prepared proniosome powder which can be measured directly to determine the percentage of EE. To determine the E.E. percent, the niosomal suspension (10ml) was taken as a sample to centrifuge it for one hour in a cooling centrifuge (TJ-6, BECKMAN, UK) at 4 degrees Celsius at 7000R.P.M.  To get rid of any surface drug, the residue hence obtained was washed (1% Tween-80 solution) and supernatant was discarded. The centrifuging   process was repeated again. A 1:1 ratio of chloroform and ethanol (v/v) was taken to blend the residue obtained after the second centrifugation  process for estimation14-16 (validated U.V method)


Vesicle size measurement (V.Z):

For the measurement of vesicle size, initially a glass beaker having 5ml of niosomal suspension and 500ml distilled water (Double-distilled) was stirred at 600 R.P.M. After that the measurements for vesicle size were taken using a particle size analyser17 (Malvern-Mastersizer 2000 instruments Ltd., UK.). (having triplicate mean±SE). 


In-vitro release of EVF proniosomes:

The proniosomal powder infused with EVF was subjected to dissolution  test for acknowledging absorption  in intestine using a simulated acidic gastric environment of  pH 1.2. The study was conducted using a Paddle apparatus (DS-8000) USP type-ii from lab India at a speed of 50 R.P.M. and a temperature of around 37 degrees Celsius (±0.5C). 900ml of the dissolution medium was taken for the experiment and during the paddling process some aliquot (5ml) was collected regularly up to an interval of 2 hours18. After the aliquot was removed, same amount of dissolution  medium was reintroduced  in the container  for maintaining constant  volume. Membrane filters (MILIPORE USA, 0.22µm) was used to filter  out the samples and then proceed for UV analysis  having a wavelength  of 247nm.


Solid State Characterization:

Scanning Electron Microscopy (SEM).:

A scanning electron microscope was used for determining the surface characteristics of proniosomal-drug combination powder .Japanese technology based HITACHI S.E.M of MODEL S-4100 was used for the purpose. A thin gold layer was coated on the samples to make them conductive to electricity and the fixed on the brass stub using a double -side adhesive tape. The images were taken at 15 KEV for further analysis19,20.


Differential scanning calorimetry (DSC):

DSC-6, Perkin Elmer calorimeter was used for conducting D.S.C. analysis of the selected formulation MPA4. Its molecular state was analyzed in the form of D.S.C curves after performing the calorimetry on EVF (pure form), proniosome powder and maltodextrin. A nitrogen purge was given at 50mL/min considering the temperature at 40 to 4500C for conducting the measurements. Keeping the rate of cooling and heating at 250C/min and 10C/min, each sample was kept on a pan made with aluminum and then crimped using a cover (aluminum).

Fourier transform infrared (FT-IR) spectroscopy:

Keeping the range of scanning and resolution at 4000–500cm-1 and 4 cm-1 respectively, the conventional KBr-pellet method was applied to obtain the Infrared spectra of the optimal formulation of proniosome powder (MPA4), non-ionic surfactant, maltodextrin and EFV. The FT-IR spectrophotometer used for the purpose was sourced from Thermo Scientific, U.S.A.


Ex-vivo permeation studies:

For the permeation study, rats (Male wistar rats having 180- 200gm were sourced from Mahaveera Enterprises (146-CPCSEA no: 199; Hyderabad, India) were used in controlled environmental condition where temperature was maintained and food and water was continuously provided in separate closed cages according to the guidelines of I.A.E.C (Institutional Animal Ethical Committee), St. Peter’s Institute of pharmaceutical sciences before using them from the experiment. For the experiment, Krebs–Ringer solution was used to clean up the intestine (removal of intestinal contents and mucus) after removing an ileum segment from the abdomen. The optimum proniosomal formulation (MPA4) was mixed with phosphate buffer (pH 6.8 ) which equals to 5ml drug was introduced to lumen at one end and the other end was secured tightly for the drug to get absorbed. Proper environmental conditions at 37 degree celsius were maintained with continuous aeration in an organ-bath. To maintain the volume of the buffer (50ml) in the receptor chamber, an aliquot of 1ml was removed at equal intervals and equal volume of solution was reintroduced21. For comparison study, the samples were processed with the same quantity of ethanol and then centrifugation was done to establish the presence of the same amount of EFV in the supernatant by pure drug dispersion method using U.V. method. Euthanasia and carcass disposal was done according to the protocols.



Solid state Characterization Study:

The molecular interactions between drug and carrier were studied using Scanning electron microscopy, differential scanning calorimetry, and Fourier transform infrared spectroscopy. Maltodextrin was selected as a carrier for proniosomepowders. The thermotropic behaviour and the physical state of the drug in proniosome powder were ascertained from the DSC thermograms of drug, maltodextrin and proniosome formulation (MPA4). It is apparent from that the drug possess crystalline behaviour as it show sharp intense peak at 1350C-1380C corresponding to its melting point.. It is evident from the SEM images that the maltodextrin possess porous surface with high surface area which enables it to be used as an efficient carrier for the lipid loading (Fig. 5). All these peaks have appeared in proniosome formulation at 2922cm-1(O–H stretching), 1735cm -1 (C=O stretching), 1464cm -1 (C=C Aromatic stretching), indicate no chemical interaction between Efavirenz maltodextrin and span 60.


Box-Behnken Experimental Design:

As mentioned earlier, responses on C.D.R percentage, Vesicle size and E.E. percentage was recorded after constructing the B.B.D on the 3 factors i.e cholesterol, Span-60 and Maltodextrin. Linear regression was used to study the responses received after analysing the effect of these factors. The predicted r2(obtained from quadratic model)hence obtained can be used to analyse the response. Fully modelled polynomial equation was obtained after undergoing multiple regressions of all the dependent variables. All dependent variables were exposed to multiple regressions to get a second-order polynomial equation (full model). X2X3, X1X3 and X1X2 are called the interaction terms .The factors X3, X2 andX1 , when averages the change to high level from low level is considered as an important effect. When interaction terms are encountered, it means the change in response had occurred after the alterations in 2 factors. By removing certain terms, an effort was made to improve the original model. The formulations (15 number) and their respective responses are recorded in table 3. The number of runs in the experiment is also 15 which is an added advantage since it saves time and effort devoted for the research .Being a structural lipid, cholesterol increases the E.E. percent of vesicles and raise the membrane stability. The pros of using maltodextrin as an ingredient in the formulation are many; less solubility in drug loaded-mixture solution, high solubility in Aqueous media , is nontoxic and safe for long run. Thus due its better drug loading capacity (due to better hydration properties ) it is more suitable as a carrier for pure drug. Its preparation was done by incorporating slurry-method in the experimental investigation.


Table No 2:Box-Behnken Design for Maltodextrin based Efavirenz loaded Proniosome (MPA)


Maltodextrin (X1)

Span60 (X2)

Cholesterol (X3)

Y1 (EE) % (W/W)

Y2 VD (nm)

Y3 % Drug Released











































































































Entrapment efficiency (EE%):

Entrapment efficiency of EFV proniosomal preparations ranged between 86.59±1.68 and 59.23±0.63 as shown in table 4. The equation given below was obtained by conducting multiple regressions on the given range of values for the factors X3,X2 AND X1 at various levels.


EE%=70.46+3.41X1-0.6562X2-0.0588X3+6.55X1X2- 0.02X1X3+1.85X12+4.34X22+2.28X32…………….(1)


From the equation, it can be observed that, The coefficients of the interaction coefficients X1X3 and X1X2 indicated a positive effect on Entrapment Efficiency percent. While the coefficient of X3 (Maltodextrin) indicates a negative effect on E.E. percent. It means E.E. and maltodextrin concentration become inversely proportional at that point. The lowest value is indicated for X2's (surfactant) coefficient having p>0.05 and b2 = 0.82 which suggests that the factor doesn't contribute to E.E. percentage significantly. Finally, it's a good fitting model because the value of the determination coefficient (R2) derived is 0.991. All the responses are expressed both in Counter plot and 3D plot (Figure-4)


Vesicle size measurement:

The vesicle size varied between 544±11.2nm and 275± 21.80nm in a proniosome formulation as mentioned in table 2. By increasing the hydrophilic balance of surfactant used, mean size of niosomes also increased. This was due to the fact that surfactant free energy varies directly with hydrophobicity. That means, higher the hydrophobicity, higher will be the free energy of surfactant. So, when span-60 (H.L.B. -4.7) was taken for surfactant preparation, the vesicles in the niosomes hence formed were found to have a mean size of 372 nm.In the formulation, the bigger vesicle sizes (>100 nm) might be a result of high content of cholesterol. Cholesterol reduces vesicle phase-transition temperature peak by increasing the lipid bilayers width which in turn impacts its fluidity negatively. Smaller vesicle size could be due to lesser amount of surfactant used because in thin and uniform film of the surfactant mixture, hydration was more convenient. A Quadratic model was constructed on VZ and for identifying various terms of the model,. Equation represents VZ having a determination coefficient (R2 ) of 0.90. The regression equation (2nd order) was formed after implementing multiple regressions on VZ values at various levels of X3,X2 AND X1.Effect of all independent variable on responses are expressed in 3D Plot (Figure-3)


Figure:1 a) Entrapment Efficiency b)Vesicle diameter


Figure:2 s Particle size distribution for Optimized formulationb. SEM image for Optimized formulatio


In-vitro release study:

The Effect of independent factors on EFV is expressed by following polynomial equation


CDR%=90.28-0.8187X1+2.31X2+1.43X31.26X1X21.08X1X3+1.29X2X3+4.80X12+1.28X22 +2.95X32


The amount of EFV released at 120 minute was between 102±1.2% to 86±1.4% as given in table no 2 Also, as shown in figures 6a,6b and 6c ,the range of values obtained as coefficients in the equation indicates an effect of all factors to the percentage of EFV. released. The positive coefficients (X2, X3 and X2X3) affects the EFV. release percent in a positive way while a negative coefficient (X1 and X1X2) indicates a detrimental effect on the same. Thus its clear that a high value of coefficient can predict the EFV. release percent. In this case the value is b2 which is the coefficient of the factor X2. The model is well fit according to The determination coefficient (R2 ) obtained from the second order equation which exhibited 0.9594 as result. Responses are expressed in 3D (Figure:5)


Figure 3: Surface response 3D plots for vesicle size




Figure 4: Surface response 3D plots for EE%


Figure 5: Surface response 3D plots for Drug Release%


Ex-vivo intestine permeation study:

Ex vivo study for permeation of the drug formulation was conducted on the ileum portion of rat intestine to have an insight on the absorption rate. Apart from dissolution rate, permeation rate in GI tissues is also important while considering the oral route of administering the drug. Rat tissue is selected for the experiment because most of the drugs get absorbed from the small intestine of a living organism and rats are anatomically quite similar to the human body. Figure 7 represents the calculated C.A.P (cumulative amount permeated) inside the GI tract after inserting a test amount of proniosomal formulation into it. For MPA4 formulation, (P<0.01),the C was found to be 2614±215 µg which is definitely higher than C.A.P from Pure drug i.e. 1500±114µg. This can be observed from table no3 too. The Proniosomalformulation exhibited higher permeation rate as compared to Pure drug Also, flux was noticed to increase as compared to control for proniosomal formulation and Pure drug



Figure:6 Comparison graph for Ex-vivo permeation of MPA4 with pure drug in rat intestine



It is evident from the experiment that; slurry method can be adopted for loading EFV. in maltodextrin based proniosomal formulation. The optimal combination of cholesterol and span-60 in equal proportions of the blend MPA4 is proven to demonstrate high E.E., surface charge and low vesicle size, the solid-state characterization indicates that conversion to molecular and amorphous states has been achieved from crystalline state. Also, the dissolution behaviour (in- vitro) and flow properties were as per standards. Apart, the absorption of the drug formulation is better inside the GI tract as concluded from the experiment in rat intestine from ex-vivo permeation studies. The better absorption is due to the presence of proniosomes in the formulation; which proves its potential as a carrier of EFV. through oral route. However, more in-vivo studies are required to be explored to increase the bioavailability of EFV by the use of proniosomes as carriers.



I would like to thank Management, Principal of Joginpally B.R Pharmacy College for providing facilities required to carry out this work.



The authors declare no conflict of interest



1.     Singh, P., Verma, A., Mittal, P. and Khinchi, M.P., 2013. Self Emulsifying Drug Delivery System: An Approach To Enhance Oral Bioavailability. Asian Journal of Pharmaceutical Research and Development, pp.178-193.

2.     Figueroa-Campos, A., Sánchez-Dengra, B., Merino, V., Dahan, A., González-Álvarez, I., García-Arieta, A., González-Álvarez, M. and Bermejo, M., 2020. Candesartan cilexetil in vitro–in vivo correlation: predictive dissolution as a development tool. Pharmaceutics, 12(7), p.633.

3.     Babadi, D., Dadashzadeh, S., Osouli, M., Abbasian, Z., Daryabari, M.S., Sadrai, S. and Haeri, A., 2021. Biopharmaceutical and pharmacokinetic aspects of nanocarrier-mediated oral delivery of poorly soluble drugs. Journal of Drug Delivery Science and Technology, 62, p.102324.

4.     Ahad, A., Raish, M., Al-Jenoobi, F.I. and Al-Mohizea, A.M., 2018. Sorbitane monostearate and cholesterol based niosomes for oral delivery of telmisartan. Current drug delivery, 15(2), pp.260-266.

5.     Baig, M.R., Shahiwala, A. and Khan, S.A., 2018. Sensible Use of Technologies to Increase Solubility and Bioavailability in Formulation Development. Advancements in Bioequivalence & Bioavailability, 1(1), pp.1-4.

6.     Mohanty, D., Rani, M.J., Haque, M.A., Bakshi, V., Jahangir, M.A., Imam, S.S. and Gilani, S.J., 2020. Preparation and evaluation of transdermal naproxen niosomes: formulation optimization to preclinical anti-inflammatory assessment on murine model. Journal of liposome research, 30(4), pp.377-387.

7.     Jangam, R.P., Thombre, A.N. and Gaikwad, N.P., 2017. A review: proniosomes as a novel drug delivery system. Asian Journal of Pharmacy and Technology, 7(3), pp.166-174.

8.     Debnath, A. and Kumar, A., 2015. Structural and functional significance of niosome and proniosome in drug delivery system. International Journal of Pharmacy and Engineering, 3(3), pp.621-637.

9.     Upadhye, S. and Rafik, I.N., 2020. Proniosomes: A novel vesicular drug delivery system. Am. j. PharmTech res, 10(2), pp.260-273.

10.   Mogatle, S., 2008. African traditional medicines-antiretroviral drug interactions: the effect of african potato (Hypoxishemerocallidea) on the pharmacokinetics of efavirenz in humans (Doctoral dissertation, Rhodes University)

11.   Ganta, K.K., Mandal, A. and Chaubey, B., 2017. Depolarization of mitochondrial membrane potential is the initial event in non-nucleoside reverse transcriptase inhibitor efavirenz induced cytotoxicity. Cell biology and toxicology, 33(1), pp.69-82.

12.   Chiappetta, D.A., Hocht, C., Taira, C. and Sosnik, A., 2010. Efavirenz-loaded polymeric micelles for pediatric anti-HIV pharmacotherapy with significantly higher oral bioavailability. Nanomedicine, 5(1), pp.11-23.

13.   Ismail, S. and Khattab, A., 2018. Optimization of proniosomal itraconazole formulation using Box Behken design to enhance oral bioavailability. Journal of Drug Delivery Science and Technology, 45, pp.142-150.

14.   Khudair, N., Agouni, A., Elrayess, M.A., Najlah, M., Younes, H.M. and Elhissi, A., 2020. Letrozole-loaded nonionic surfactant vesicles prepared via a slurry-based proniosome technology: Formulation development and characterization. Journal of Drug Delivery Science and Technology, 58, p.101721.

15.   Zhou, Y., Li, W., Chen, L., Ma, S., Ping, L. and Yang, Z., 2010. Enhancement of intestinal absorption of akebia saponin D by borneol and probenecid in situ and in vitro. Environmental toxicology and pharmacology, 29(3), pp.229-234.

16.   Samein, L.H., 2014. Preparation and evaluation of nystatin-loaded solid-lipid-nanoparticles for topical delivery. Asian Journal of Pharmaceutical Research, 4(1), pp.44-51.

17.   Sharma, A., Guarve, K. and Singh, R., 2021. Application of Box–Behnken Design and Desirability function in the Optimization of Aceclofenac-Loaded Micropsonges for Topical Application. Research Journal of Pharmacy and Technology, 14(12), pp.6295-6303. DOI: 10.52711/0974-360X.2021.01089

18.   Jangam, R.P., Thombre, A.N. and Gaikwad, N.P., 2017. A review: proniosomes as a novel drug delivery system. Asian Journal of Pharmacy and Technology, 7(3), pp.166-174.

19.   Raju, T.G., Ramya, M.G., Rajesh, A., Kathirvel, S. and Gupta, S.K., 2014. ICH Guideline Practice-a Validated Stability-Indicating HPLC Method for the Determination of Efavirenz in Dosage Form. Research Journal of Pharmaceutical Dosage Forms and Technology, 6(1), pp.7-14.

20.   Sharma, A., Guarve, K. and Singh, R., 2021. Application of Box–Behnken Design and Desirability function in the Optimization of Aceclofenac-Loaded Micropsonges for Topical Application. Research Journal of Pharmacy and Technology, 14(12), pp.6295-6303. DOI: 10.52711/0974-360X.2021.01089

21.   Kaushal, A., Arora, S., Singh, S. and Sharma, N., 2020. Assessing the impact of formulation variables on dissolution profile of sustained release tablet of metformin hydrochloride by quality by design approach. Research Journal of Pharmacy and Technology, 13(5), pp.2350-2358.





Received on 10.11.2021          Modified on 14.02.2022

Accepted on 23.04.2022        © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(2):669-675.

DOI: 10.52711/0974-360X.2023.00114