The Major Challenges Facing The Pharmaceutical Industry Biology Essay

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One of the major challenges facing the pharmaceutical industry today is finding new ways to raise effectiveness, decrease costs at the same time as still ultimately developing new therapies that enhance human health. To lend a hand address these challenges the consumption of analytical technologies and high-throughput automated platforms has been employed; in order to perform more experiments in a shorter time frame with increased data quality.

In recent years, significant technological advances have been made in particle chemistry performance, system optimization, detector design, and data processing and control. When brought together, the individual achievements in each discipline have created a step-function improvement in chromatographic performance. Ultra performance liquid chromatography (UPLC) is a new category of analytical separation science that retains the practicality and principles of HPLC, while increasing the overall interlaced attributes of speed, sensitivity and resolution.

ACQUITY Ultra Performance LCâ„¢ Systems take advantage of technological strides made in particle chemistry performance, system optimization, detector design, and data processing and control. When taken together, these achievements have created a step-function improvement in chromatographic performance. Defined as UPLCâ„¢, this new category of analytical separation science retains the practicality and principles of HPLC while increasing the overall interlaced attributes of speed, sensitivity, and resolution.

Fig. 1: UPLC Diagram

In this thesis the scope has been to create improved high sensitive liquid chromatography methods for the quantification of bulk drugs in order to achieve the better performances of the different events in the analytical chain to know the purity and assay. The specific topics studied in this thesis are described below.

The thesis comprises of 7 chapters as described below

Chapter-1: Introduction

The chapter describes the experimental procedures adopted for analytical method development, method validation and its application to analysis of pharmaceutical drugs. A fully logic, rational and systematic approach was followed for UPLC method development based on chromatographic principles (Figure-2). All the procedures adopted were as per US FDA guidelines.

Fig. 2: Over view of systematic process in Analytial Development

Fig. 3: Over view method validation parameters

Chapter-2: Literature Survey

Chapter-2 provides a brief description about the category, solubility, stability and Quantification in bulk drugs about the selected molecules for these thesis

1. 5-alpha reductase drug - Compound-A (Finasteride ),

2. 5-alpha reductase drug - Compound-B (Dutasteride),

3. Anti migraine drug -Compound C (Zolmitriptan)

Anti migraine drug -Compound D (Rizatriptan benzoate)

Chapter-3: Finasteride

In this chapter the category of 5-alpha reductase inhibitors were considered for the research work. In this category Finasteride compound was considered for the development and validation Purity and Assay method. Chemically it is described as N-(1,1-dimethylethyl)-3-oxo-(5α,17β)-4-azaandrost-1-ene-17-carboxamide. The emperical formula is C23H36N2O2. Molecular weight is 372.55 (Fig:4). It is a specific inhibitor of steroid Type II 5α-reductase, an intracellular enzyme that converts the androgen testosterone into 5α-dihydrotestosterone (DHT).

Benign prostate hyperplasia (BPH) is an androgen-dependent, nonmalignant growth of the periurethral prostate gland that results in enlargement of the prostate gland and urinary obstruction. Prostate cancer, the most common cancer among men over 50years with increasing prevalence with age, is the leading cause of cancer death . Finasteride (FIN) (CAS 98319-26-7), a member of the 4-azasteroid family, is a potent inhibitor of 5-alpha-reductase,this synthesizes androgendihydrotestosterone (DHT) through the reduction of testosterone.

Fig. 4: Chemical Structure of Finasteride

After review so many analytical journals and literatures, we observed all the published analytical methods are having higher runtime and mobile phase having different composition of solvents ,gradient program and high injection volume (20µL), no RP-UPLC method for quantification of Finasteride and its related impurities in Pharmaceutical bulk drugs were not published. Here we were present first time stability indicating RP-UPLC method for Quantification of Finasteride and its related impurities in API bulk drugs with shorter runtime 16.0 min, low injection volume, low flow rate (0.22 ml/min) and solvent usage also less when compare to existing published methods. The newly developed method was fully validated as per ICH guide lines. This RP-UPLC method was successfully used for routine analysis of API bulk drugs as well as formulations in Pharmaceutical industries.

The linearity range of Finasteride assay method was constructed using calibration standards (viz., 0.0025-0.15 mg/mL). The % accuracy of Finasteride observed was within 99.1 -100.7 at 50%,100% and 150% level; while the method precision %RSD at 100% level is 0.25. Recoveries of Finasteride impurities were estimated at 0.05, 0.10,0.15,0.20,0.25 and 0.30 mg/mL and the mean recovery of Impurities was 101.3, 98.9,101,100.2,100 and 100.70%, respectively. Finasteride was subjected to stress under the degradation conditions i.e base and peroxide hydrolysis and remaining stress conditions like Thermal, UV, Visible, acid and water hydrolysis is stable. This validated method was used routine analysis of quantification of assay and its related impurities in pharmaceutical bulk drugs.

Chapter-4: Dutasteride

In this chapter the category of 5-alpha reductase inhibitors were considered for the research work. In this category Dutasteride compound was considered for the development and validation Purity and Assay. Chemically known as (5α, 17β)-N-{2,5 bis(trifluoromethyl)phenyl}-3-oxo-4-azaandrost-l-ene-17-carboxamide (Fig:5), is a synthetic 4-azasteroid compound with anti androgenic activity. Dutasteride is used to treat benign prostatic hyperplasia in men having an enlarged prostate gland and in the treatment of male pattern baldness. It belongs to a class of drugs called 5α-reductase inhibitors, which competitively and specifically inhibits type 1 (active in the sebaceous glands of most regions of skin and liver) and type 2 (primarily active in the reproductive tissues like prostate, seminal vesicles, epididymides, hair follicles and liver) isoforms of 5α-reductase, an intracellular enzyme that converts testosterone to 5α-dihydrotestosterone. The decrease in dihydrotestosterone levels may mitigate or prevent enlargement of the prostate gland. Dutasteride does not bind to the human androgen receptor.

Fig. 5: Chemical Structure of Dutasteride

After review so many analytical journals and literatures, we observed all the published analytical methods are having higher runtimes and mobile phase having different compositions of solvents ,gradient program and high injection volume (20µL), no RP-UPLC methods for quantification of Dutasteride and its related impurities in Pharmaceutical bulk drugs were not published. Here we were present first time stability indicating RP-UPLC method for Quantification of Dutasteride and its related impurities in API bulk drugs with shorter runtime 10.0 min, low injection volume, low flow rate (0.4 ml/min) and solvent usage also less when compare to existing published methods. The newly developed method was fully validated as per ICH guide lines. This RP-UPLC method was successfully used for routine analysis of API bulk drugs as well as formulations in Pharmaceutical industries

The linearity range of Dutasteride assay method was constructed using calibration standards (viz., 0.0025-0.15 mg/mL). The % accuracy of Dutasteride observed was within 99.1 -100.7 at 50%, 100% and 150% level; while the method precision %RSD at 100% level is 0.25. Recoveries of dutasteride impurities were estimated at 0.05, 0.10,0.15,0.20,0.25 and 0.30 mg/mL and the mean recovery of Impurities was 98.9, 96.1,97.4,94.7,94.5 and96.1%, respectively. Dutasteride was subjected to stress under the degradation conditions i.e acid and base hydrolysis and remaining stress conditions like Thermal, UV, Visible, peroxide and water hydrolysis is stable.

This validated method was used for routine analysis for quantification of assay and its related impurities in pharmaceutical bulk drugs and dosage forms.

Chapter-5: Zolmitriptan

In this chapter the category of Anti migraine drug were considered for the research work. In this category Zolmitriptan compound was considered for the development and validation Purity and Assay method. Chemically it is described as (S)-​4-​({3-​[2-​(dimethylamino)​ethyl]-​1H-​indol-​5-​yl}​methyl)-​1,3-​oxazolidin-​2-​one. The empirical formula is C16H21N3O2. Molecular weight is 287.16 (Fig-6).

Zolmitriptan is a synthetic tryptamine derivative and appears as a white powder that is readily soluble in water. It is a selective serotonin receptor agonist of the 1B and 1D sub types drug, used in the acute treatment of migraine attacks with or without aura and cluster headaches.

Fig. 6: Chemical Structure of Zolmitriptan

After reviewing of so many analytical journals and literatures, we observed all the published analytical methods are having higher runtimes and mobile phase having different compositions of solvents ,gradient program and high injection volume (20µL), no RP-UPLC methods for quantification of Zolmitriptan and its related impurities in Pharmaceutical bulk drugs and formulations were not published. Here we were present first time stability indicating RP-UPLC method for Quantification of Zolmitriptan and its related impurities in API bulk drugs with shorter runtime 10.0 min, low injection volume, low flow rate (0.3 ml/min) and solvent usage also less when compare to existing published methods. The newly developed method was fully validated as per ICH guide lines. This RP-UPLC method was successfully used for routine analysis of API bulk drugs as well as formulations in Pharmaceutical industries.

The linearity range of Zolmitriptan assay method was constructed using calibration standards (viz., 0.05-0.15 mg/mL). The % accuracy of zolmitriptan observed was within 99.1 -100.7 at 50%, 100% and 150% level; while the method precision %RSD at 100% level is 0.25. Recoveries of zolmitriptan impurities were estimated at 0.05, 0.10,0.15,0.20,0.25 and 0.30 mg/mL and the mean recovery of Impurities was 99.07, 98.4, 99.9, 98.7, 100 and 98.9%, respectively. Zolmitriptan was subjected to stress under the degradation conditions i.e acid,base and peroxide hydrolysis and remaining stress conditions like Thermal, UV, Visible and water hydrolysis is stable.

This validated method was used for routine analysis for quantification of assay and its related impurities in pharmaceutical bulk drugs and dosage forms.

Chapter-6: Rizatriptan benzoate

In this chapter the category of Anti migraine drug were considered for the research work. In this category Rizatriptanbenzoate compound was considered for the development and validation Purity and Assay method. Rizatriptan is a 5-HT1 agonist triptan drug for the treatment of migraine headaches. Chemically it is described as N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-ndole-3-ethanamine monobenzoate. The empirical formula is C15H19N5.C7H6O2. Its molecular weight is 391.47 and its chemical structure shown in Fig.7

Fig. 7: Chemical Structure of Rizatriptan Benzoate

Significant number of methods has been reported for the analysis of Rizatriptan in human plasma and serum by liquid chromatography and liquid chromatography/mass spectrometry. Quantitative analysis of formulated drug product by micro emulsion electro kinetic capillary chromatography (MEEK) was also reported. There are several HPLC methods have been reported for the analysis of Rizatriptan and its potential process impurities with higher runtimes and injection volumes. The UPLC enables improving the sensitivity and selectivity with a significantly lower turnaround time. Therefore, it was the need of the honor to develop a simple, specific, rapid, economic and sensitive and stability indicating analytical method for the quantification in bulk drugs.

Here we were present first time stability indicating RP-UPLC method for Quantification of Rizatriptan and its related impurities in API bulk drug with shorter runtime 13.0 min, low injection volume, low flow rate (0.3 ml/min) and solvent usage also less when compare to existing published methods. The newly developed method was fully validated as per ICH guide lines. This RP-UPLC method was successfully used for routine analysis of API bulk drugs as well as formulations in Pharmaceutical industries.

The linearity range of Rizatriptan assay method was constructed using calibration standards (viz., 0.05-0.15 mg/mL). The % accuracy of rizatriptan observed was within 99.1 -100.7 at 50%, 100% and 150% level; while the method precision %RSD at 100% level is 0.25. Recoveries of rizatriptan impurities were estimated at 0.05, 0.10,0.15,0.20,0.25 and 0.30 mg/mL and the mean recovery of Impurities was 100.9, 102.2, 100.2, 105.7, 101 and 100.7%, respectively. Rizatriptan was subjected to stress under the degradation conditions i.e peroxide hydrolysis and remaining stress conditions like Thermal, UV, Visible acid, base and water hydrolysis is stable.

This validated method was used for routine analysis for quantification of assay and its related impurities in pharmaceutical bulk drugs and dosage forms.

Chapter-7: Summary & Conclusion

Chapter 7 describes the brief summary of the above categories of the drugs including analytical method development, method validation and its application to routine analysis study followed by conclusion.

List of Publications

Y.KotiReddy, G.V. Subba Reddy, K.N. JayaVeera, Kishore Kumar Hotha. A Stability indicating UPLC Method for Finasteride and Its Related Impurities. American Journal of Analytical Chemistry, Vol.No.3 (11), Year 2012, Pages (pp) 737-745.

Y.KotiReddy, G.V. Subba Reddy, K.N. Jaya Veera, Kishore Kumar Hotha.

UPLC Method For The Determination Of Rizatriptan Benzoate And Its Related Impurities. International Journal of Analytical and Bioanalytical Chemistry, Vol.No.2 (4), Year 2012, Pages (pp) 228-234.

Y.KotiReddy, G.V. Subba Reddy, K.N. Jaya Veera. A New Stability indicating RP-UPLC Method for Related substances in Zolmitriptan. African Journal of Scientific Research, Vol.No.1 (1), Year 2011, Pages (pp) 50-62.

Y.KotiReddy, G.V.Subba Reddy, K.N.JayaVeera, Kishore Kumar Hotha. A Stability indicating UPLC Method for Dutasteride and Its Related Impurities. American Journal of Pharmtech Research, Vol.No.2 (6), Year 2012, Pages (pp) 702-715.

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