Swaroop Tech.Consultancy was engaged by many pharma industries and Universities in designing and developing a Right Process at R & D level and also in improving the existing processes. Some such cases have been listed here.
In a pharma company , while developing the process they wanted to improve the yield and purity of the product before they proceed further. The Scientists tried a lot by changing some of the process parameters like temperature, mole ratio of the reactants etc. by conducting various experiments ( 35 nos) with conventional method. A maximum yield of 45% could be obtained and the changes in the process parameters were only increasing the impurities in the out put but not yield and the project was abondoned .
The company asked the Swaroop Tech.Consulatncy to render the consultancy on the same project as to how to improve the yield and reduce the impurities and there by improve the purity of the product . Eight DOE experimental plan by use of SigmaTech was given to them to conduct the experiments and report the results. On analysis of the result by SigmaTech, the process models were developed by the software for yield and purities and simulated for improved yield and purity and the process parameters for the improved yield and purity were predicted . The scientists were asked to confirm the parameters and out puts by experimentation . They confirmed to be right and implemented it.
|Sno||No of experiments||Yield||Purity|
|1||With traditional method done by the plant.||35||45%|
|2||Improved Process by consultancy resulted .||8||66%||95%|
|3||Reduction in time cycle||75%|
On getting convinced by the success of this project, our consultancy was engaged for 6 more projects . Out of 6 projects 5 were success fully completed and the last one could not be completed as there had been some mistake on the part of conducting experiments by the scientist. Then the Training/ work shop was conducted as desired by the company as package with SigmaTech. By then the scientists had enough experience to design and develop the process by them selves.
Analytical Research Laboratory, Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapur, AP, India – 515721, wanted a consultancy to develop the method for HPLC.
Reverse Phase high performance liquid chromatographic HPLC method for routine analysis of Etofenamate (ETF) in dosage form has been developed using experimental design. Design of Experimental (a statistical) method adopted resulted in a considerable improvement in chromatographic performance using fewer experiments, without additional cost for column. A polynomial process model was obtained for retention time (Y). The statistical analysis revealed that two factor interactions were quite significant and hence Central Composite Design was used. The non linear process model was used to construct contour diagrams, two dimensional response surface plots. Optimum valves of pH, % aqueous in mobile phase composition and flow rate were obtained through contour diagrams for the targeted values of retention time. The predicted data from contour diagram for retention time were verified actually and it satisfied with actual experimental data. A HPLC system equipped with a C18 column (250mm×4.6mm, 5µm), a binary pump and photodiode array detector were used in this work. The optimized method was achieved at 1.2 ml/min flow rate using mobile phase composition of methanol and water 85:15, % v/v, pH adjusted to 6.5. The method was validated and used for the quantification of active ingredients in dosage forms.
|Sno||No variables||No of eperiments||Yield||impurities|
|1||With Conventional method||4||50||71%||Not measured.|
|2||With DOE application Acetone & potassium hydroxide||4||16||87.98%||Bromo: 2.15%
|3||Reduction in time cycle||65%|
|4||Improvement in yield||24%|
In a condensation reaction six reactants are involved to produce a pyramidon. One of the main reactant was kept constant as a one mole and other five reactants were changed during the reaction. The yield was 38% to 43% in the plant against an expected yield of 60%. Since it forms an isomer and desired isomer can not be more than 60% at the reaction temperature. By and large many process parameters were standardized like pH, temperature, time of reaction etc and kept constant by detailed study. Even then the variation in the out put remained a problem resulting a lower level of productivity . The variation of the process could not be eliminated as the source of the variation could not be identified. Since the plant was to be doubled to its capacity, yield was a critical quality attribute before expansion of the plant takes place. Hence CPPs were to be found out obtain a right and robust CQA.
A DOE plan of 15 experiments was given and the process model was built on the analysis of the experimental results. By simulating the process model with software SigmaTech , two sets of higher yield were obtained as given below.
|1||1.091 mole ratio||1.96 to 2.18 moles||1.0195 mole ratio||60.00%|
|2||1.023 to 1.091 mole ratio||1.74 moles||1.0195 mole ratio||57.60%|
Though the second set 57.3% was lower than theoretical yield of 60%, it gave a robust process in a graphical representation with a wide range of variable X1. Hence this Robust process parameters were followed as CPPs to obtain a CQA.
one R & D Unit of a Polymer Lab , at Faridabad had tried already with several runs to develop a chemical in the lab scale. Highest yield obtained was 61%. They were finding it difficult to decide which of the solvents and catalysts were more effective along with time and temperatures of the process . The Management wanted the product with higher yield . Hence they wanted the consultancy from Swaroop Tech.Consultancy in arriving at the solution . A lengthy deliberations/ brain storming session among the scientists led to the following factors for the improvement of the process.
The time of maintenance from 12 hours to 24 hours, and temperature from 50C to 80C were to be decided.
Since the mole ratio of the main reactants was to be taken at constant level which was well known to them, it was not a variable to be considered.
Ø Among the neutralizing agents, there was no special consideration and hence sodium carbonate the cheapest one was considered.
Ø Both the catalysts one at lower level and the other at higher level was considered in qualitative mode.
Ø Solvents: Among alcohols, already isopropyl alcohol was tried. Since the compound was least soluble in water, it was not preferred. Hence acetone was thought of as solvent. Since the boiling point of acetone is around 60C, where as the temperature as high as 80c was to be maintained for completing reaction/ conversion, MIBK was considered as the most suitable one .
Thus it was required to select one out of two solvents, one out of two catalysts, and the best temperature and time.
Finally KI and Amine as two catalysts , IPA and MIBK as two solvents were considered for screening effective materials along with time and temperature of reaction. Taguchi method was applied with eight experimental plan and experiments revealed that yield could be improved to 80% and analysis by SigmaTech indicted that catalyst KI, solvent API were better performing. Time of reaction from 12 o 24 hrs has not contributed to yield but increase in temperature has significant positive contribution on yield. Hence selecting KI as catalyst, IPA as a better solvent , fixing 12hrs as time of reaction ( resulting 2 batches a day doubling capacity of plant) and increase in temperature beyond 80C was suggested with 8 more experimental plan to go beyond 80% yield. The scientists got highest yield and wanted a training on these methods. Swaroop ech. Consultancy gave training along with software as a package.
A Research Scholar in Bio Technology Deptt. Of Osmania University was working to develop a process by fermentation process to obtain Lactic acid from Bagasse. It involved 15 process and operating in put variables to plan the experimentation and execute the work. It was estimated that at least 250 experiments were required and needs about 30 months time to complete the project work to get awarded PHD. The research scholar had attended a seminar conducted by Swaroop Tech.Consultancy on Process Design and methods. After the seminar he wanted us to guide their project with statistical methods to reduce the time cycle while screening in put materials.
Similarly a number of projects in Bio Technology and pharmacy were guided and got completed at other Universities like Andhra University, Jawahar lal Nehru Technology University and colleges.
The production process designed with traditional method was so much in-consistent that the yield of the product used to vary from 40% to 80% . The factors affecting so much variation was not known. Any no of changes in the process did not give consistent results. Swaroop Tech. consultancy has given a 11 experimental plan with DOE to conduct the experiments and send the observed the results. On analysis it was found that it was possible to obtain consistent results of 79% yield and the plant was asked to confirm and implement it.
|Sno||No o variables||No of experiments||Yield||Purity|
|1||Existing||3||40% – 80% highly inconsistent|
|2||With DOE||3||11||79% consistent||97%|