Alfuzosin Hydrochloride And Dutasteride In Tablets Biology Essay

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ABSTRACT

This chapter describes method development and validation of UV First Derivative Zero Crossing method for simultaneous determination of Alfuzosin Hydrochloride and Dutasteride in tablet dosage forms.

AIM

The main aim of the present study is to develope a simple, sensitive and cost effective UV spectroscopic method for the simultaneous estimation of Alfuzosin Hydrochloride and Dutasteride in tablets, on the basis of zero Crossing measurement. Validation of the developed method for routine analysis of Alfuzosin Hydrochloride and Dutasteride in tablets for quality control laboratories.

RATIONALE

Alfuzosin Hydrochloride is an alpha-adrenergic blocker used to treat benign prostatic hyperplasia (BPH). It works by relaxing the muscles in the prostate and bladder neck, making it easier to urinate Dutasteride belongs to a class of drugs called 5-alpha-reductase inhibitors, which block the action of the 5-alpha-reductase enzymes that convert testosterone into dihydrotestosterone (DHT). Recently both the drugs have been marketed in combination (Alfusin D acts on both the dynamic and the static components of BPH) in tablet dosage forms; combined oral administration has been found to be more effective than either single drug. To the best of knowledge, no derivative spectroscopic method available for simultaneous determination. Derivative spectroscopy provides a greater selectivity than common spectroscopy.

RESULT AND CONCLUSION

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A simple, accurate and precise spectroscopic method was developed for

simultaneous determination of LER and ATE in tablets using first derivative

Zero crossing method. LER shows ZCP at 231 nm while ATE shows ZCP at

250 nm. The 1D amplitude was measured at 250 nm for LER and 231 nm For

ATE and calibration curves were plotted as 1D amplitude versus concentration,

respectively. The method was found to be linear from 4-28 μg/mL for LER

(r2=0.9967) at 250 nm and 5-30 μg/mL for ATE (r2=0.9996) at 231 nm. The

within day and between day variations showed coefficient of variation (%CV)

values < 1.5% for both drugs. The limit of quantification of was found to be 2.5

and 2.77 μg/mL for LER and ATE respectively. The method was successfully

applied for simultaneous determination of both drugs in tablet dosage forms.

1.2 LITERATURE REVIEW

1.2.1 BENIGN PROSTATIC HYPERPLASIA (BPH):

It is characterized by hyperplasia of prostatic stromal and epithelial cells, resulting in the formation of large, fairly discrete nodules in the periurethral region of the prostate. When sufficiently large, the nodules compress the urethral canal to cause partial, or sometimes virtually complete, obstruction of the urethra, which interferes the normal flow of urine. It leads to symptoms of urinary hesitancy, frequent urination, dysuria (painful urination), increased risk of urinary tract infections, and urinary retention. Although prostate specific antigen levels may be elevated in these patients because of increased organ volume and inflammation due to urinary tract infections, BPH is not considered to be a premalignant lesion.

Adenomatous prostatic growth is believed to begin at approximately age 30 years. An estimated 50% of men have histologic evidence of BPH by age 50 years and 75% by age 80 years. In 40-50% of these patients, BPH becomes clinically significant.

How does BPH occur?

The prostate goes through two main periods of growth. In early puberty, the prostate doubles in size. Then, around age 25, the prostate begins to grow again and continues to grow throughout most of a man's life.

The continuing enlargement of the prostate does not usually cause problems until later in life. However, the second period of growth may, many years later, result in BPH. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

BPH rarely causes symptoms before age 40.

More than half of men in their 60s have some symptoms of BPH.

As many as 90 percent of men in their 70s and 80s have some symptoms of BPH

SYMPTOMS:

Difficulty in starting to pass urine ( hesitancy)

A weak stream of urine

Dribbling after urinating

The need to strain to pass urine

Incomplete emptying of bladder

Difficulty to control the urination urge

Having to get up several times in the night to pass urine

Feeling a burning sensation when passing urine

Passing urine mixed with blood (indication of infection)

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Treatment of BPH 

BPH may not require any form of treatment and may just be monitored for any changes or early signs of any problems. In the event that BPH has caused a urinary tract infection, the infection will be treated first with antibiotic medications and then the BPH may be treated.

There are several forms of treatment that can be used for benign prostatic hyperplasia that include medications, minimally invasive therapies, and surgery. The two types of medications currently used to treat BPH are "alpha-adrenergic receptor blockers" and "5-alpha reductase inhibitors".  These medications can prevent the prostrate gland from growing larger and may shrink the prostrate gland in some patients. 

How do Alpha blockers work:

Alpha blockers work by relaxing the smooth muscle tissue in your prostate and at the opening to your bladder. When this muscle tissue relaxes, it is easier for your urine to flow. This may help if you have difficulty starting to urinate and a weak urine stream.

Alpha blockers can start working within two to three days, and may relieve your urinary symptoms in about two to three weeks. However, these medications do not stop your prostate gland from continuing to enlarge.

Available alpha blockers include:

Cardura (doxazosin)

Flomax (tamsulosin)

Hytrin (terazosin)

Uroxatral(alfuzosin)

How do 5 alpha reductase inhibitors work

The 5-alpha reductase inhibitors work by interfering with the effect of specific male hormones (androgens) on your prostate. This may slow the growth of your prostate and can even cause your prostate to get smaller, which may help improve BPH symptoms.

Men with larger prostates may have a greater benefit from these medications than do men with smaller prostates. But, for some men, size (of the prostate that is) does not matter, and the 5-alpha reductase inhibitors may not give satisfactory results even if your prostate gets smaller.

The 5-alpha reductase inhibitors work slowly, and they may take up to six months before you notice any improvement.

Available 5-alpha reductase inhibitors include:

Avodart (dutasteride)

Proscar (finasteride)

Both an Alpha Blocker and 5-alpha Reductase Inhibitor

Depending on symptoms and the size of your prostate, your doctor may recommend a combination of an alpha-blocker with a 5-alpha reductase inhibitor. The combination of the two types of medications may help more than either medicine alone.

1.2.2 DRUG PROFILE:

Alfuzosin hydrochloride: It is an alpha-adrenergic blocker

Structure

File:Alfuzosin.svg

N-[3-[(4-amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]propyl] tetrahydrofuran- 2-carboxamide

Dutasteride: It is a 5-alpha-reductase inhibitor.

Structure

File:Dutasteride.svg

(5α,17β)-N-{2,5bis(trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide

Table 1 Physicochemical Properties of Alfuzosin HCl:

Chemical Name

N-[3-[(4-amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]propyl] tetrahydrofuran- 2-carboxamide

Molecular Formula

C19H27N5O4

Molecular Weight

389.4488

Melting Point

225°c

pKa

8.13

Log p

1.4

Solubility

Freely soluble in water, practically insoluble in methylenechoride

Colour

Alfuzosin hydrochloride is a white to off-white crystalline powder

λmax

242 nm

CAS No.

81403-80-7

Pharmacodynamic

Alfuzosin is a quinazoline-derivative alpha-adrenergic blocking agent used to treat hypertension and benign prostatic hyperplasia. Accordingly, alfuzosin is a selective inhibitor of the alpha(1) subtype of alpha adrenergic receptors. In the human prostate, alfuzosin antagonizes phenylephrine (alpha(1) agonist)-induced contractions

Pharmacokinetics

and Metabolism

Absorption is 50% lower under fasting conditions Volume of distribution 3.2 L/kg [healthy male middle-aged volunteers] Protein binding 82%-90% Metabolism Hepatic. Alfuzosin undergoes extensive metabolism by the liver, with only 11% of the administered dose excreted unchanged in the urine. Alfuzosin is metabolized by three metabolic pathways: oxidation, O-demethylations, and N-dealkylation. The metabolites are not pharmacologically active. CYP3A4 is the principal hepatic enzyme isoform involved in its metabolism.

Dose

10 mg tablet

Storage Condition

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) protect from light and moisture

Table 2 Physicochemical Properties of Dutasteride:

Chemical Name

(5α, 17β)-N-{2,5 bis(trifluoromethyl) phenyl}-3-oxo-4-azaandrost-1-ene-17-carboxamide

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Molecular Formula

C27H30F6N2O2

Molecular Weight

528.5297

Melting Point

242°c

pKa

4.9

Log p

5.45

Solubility

Freely soluble in water, practically insoluble in methylenechoride

Colour

Alfuzosin hydrochloride is a white to off-white crystalline powder

λmax

241 nm

CAS No.

164656-23-9

Pharmacodynamic

Dutasteride is a synthetic 4-azasteroid compound that is a selective inhibitor of both the type 1 and type 2 isoforms of steroid 5 alpha-reductase (5AR), intracellular enzymes that convert testosterone to 5 alpha-dihydrotestosterone (DHT). Type I 5a-reductase is predominant in the sebaceous glands of most regions of skin, including scalp, and liver

Pharmacokinetics

and Metabolism

Absorption is 60% lower under fasting conditions Volume of distribution 300 to 500 L Protein binding Highly bound to albumin (99%) and α-1 acid glycoprotein (96.6%). Hepatic. Extensively metabolized by CYP3A4 and CYP3A5 to active metabolites.

Dose

0.5 mg capsule

Storage Condition

Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture

Table 3 Marketed Combination of Alfuzosin HCl and Dutasteride:

Brand Name

ALFUSIN D

Generic Name

Alfuzosin HCl and Dutasteride

Manufacturer

CIPLA

Packing

as a strip pack of 10 tablets

Form

film-coated tablet

Strength

Alfuzosin HCl 10mg and Dutasteride 0.5mg

1.2.3 REPORTED UV SPECTROPHOTOMETRIC METHODS

Table 4 Reported UV-Spectrophotometric methods for Alfuzosin HCl and Dutasteride

Sr

No.

Application

λmax( solvent)

Linearity

Ref.

1

Optimization and Validation of Quantitative Spectrophotometric Methods for the Determination of

Alfuzosin in Pharmaceutical Formulations

575 nm

10-50 μg/mL

2

Spectrophotometric Determination of Alfuzosin HCl in Pharmaceutical Formulations with some

Sulphonephthalein Dyes

407, 413 and 412nm

1.20-38.3, 0.85-46.0 and 0.63-34.0 μg/ml

3

Extractive Spectrophotometric Determination of Alfuzosin from Its Bulk and Pharmaceutical Dosage Form

416 nm

2 to10 mg/ml.

4

Applications of colorimetric methods for the determination of cinitapride

Hydrogen tartarate in drug formulations

522.5, 510, 533, 438.6, 533.2 and 509.2nm

2‐10 1‐5 4‐20 4‐20 2‐10 10‐50 mg/ml

5

Validated UV Spectrophotometric Method For Estimation Of Dutasteride In Tablet Dosage Form

241 nm

12-28 μg/ml

6

Validated Spectrophotometric Method For Determination Of Dutasteride In Bulk Drug And

Pharmaceutical Formulations

240 nm

5-50 μg/ mL

7

Spectrophotometric Simultaneous Determination Of Dutasteride And Tamsulosin In Combined Tablet Dosage Form By First Order Derivative Spectroscopy And Area Under Curve (Auc) Spectrophotometric Methods And Its Application To Uniformity Of Content In Tablet And Capsule

247.67 nm and 232.60 nm

10-50 μg /mL and 8-40 μg/ mL

1.2.4 Aim and Objective of the present work:

Derivative spectroscopic methods are more sensitive than other spectroscopic method according to literature there is no derivative spectroscopic method reported so there is need to develop a sensitive derivative spectroscopic method which is more sensitive than simultaneous equation method so aim is to develop and validate the first derivative Zero-Crossing UV spectrophotometric method and apply that method to simultaneous determination of these drug in marketed formulation.

1.3 EXPERIMENTAL WORK

1.3.1 Chemicals and Reagents

Alfuzosin HCl and Dutasteride ALFUSIN D (CIPLA Ltd.) containing 10 mg of Alfuzosin HCl & 0.5 mg of Dutasteride were purchased from local market. Methanol of HPLC grade was purchased from Merck Ltd. (Mumbai, India). Purified Water was prepared using a Millipore Milli-Q system (Bedford, MA, USA).

1.3.2 Instrument

Spectroscopic Analysis was carried out on a JascoV-650 double beam UV-Visible

spectrophotometer with software of Spectra Manager. The zero order absorption spectra were recorded over the wavelength range of 200-400 nm, against solvent blank, in quartz cuvetts with 1 cm diameter with scan speed of 100 nm/min and fixed value of slit width is 1 nm The ordinate maximum & minimum were adjusted according to derivative values.

1.3.3 Development of UV first derivative Zero crossing method:

As the Dutasteride is Insoluble in Water 80:20 V/V Mixture of Methanol and Water were used for method development First of all, Individual Zero orders absorption Spectra of both the drugs were recorded by scanning 10 μg/ml solution. The λmax of Alfuzosin HCl and Dutasteride was found to be 240 nm & 225.5 nm respectively. We have chosen derivative spectroscopy which is based on mathematical transformation of spectra zero order curves in to derivative spectra, which allows a fast sensitive and precise resolution of a multicomponent mixture and overcomes the problem of overlapping of a multi component system. Derivative Spectroscopy on the basis of zero crossing measurement involves measurement of absolute value of total derivative spectrum at an abscissa value corresponding to the Zero Crossing wavelength of the derivative spectra of individual components, which should be only the function of the concentration of the other component. Zero crossing points of Alfuzosin HCl and Dutasteride were identified in first derivative spectra. the measurement exhibited the best linear response and have given a near zero intercept on the coordinate of the calibration graph, and is less affected by the concentration of

any other component. Alfuzosin HCl was determined by measurement of its 1D amplitude at the zero-crossing point of Dutasteride was determined by measurement of its1 D at the zero-crossing point of Alfuzosin HCl .

1.3.4 Preparation of stock solution

Primary standard stock solution of Alfuzosin HCl and Dutasteride were prepared separately by dissolving accurately weighed amount (10 mg) of drug in 10 ml 80:20 V/V (MeOH:H2O) to produce a concentration of 1.00mg/mL Working standard solution of each analyte were prepared by appropriate dilution of stock solution to get 100 μg/mL The further concentration required for constructing calibration curve were prepared daily by dilution of 100 μg/mL working standard. Stock solution of binary mixture was prepared by dissolving accurately weighed quantities of both drugs in solvent. Further dilutions of binary mixture were made to obtain QC samples.

1.3.5 Calibration standard & quality control (QC) samples

The standard calibration sample were prepared by diluting working standard solution of each analyte to yield seven different concentration over the range of

3-24 μg/mL for Alfuzosin HCl & 3-30 μg/mL for Dutasteride . Linearity was evaluated separately for each drug using the defined analytical amplitudes (1D), with appropriate seven standard solutions. The QC sample were prepared from stock solution containing binary mixture to yield the low, medium & high concentration (4,5 & 6μg/ml for Alfuzosin HCl) & (20 ,25 & 30 μg/mLfor Dutasteride).

1.3.6 Procedure for calibration curve

Absorption & derivative spectra were recorded over the range of the wavelength range 200-400 nm. Zero order spectra of standard calibration sample of 10 μg/ml of each drug were recorded against blank. First order spectra were recorded with in concentration range, the value of analytical amplitude 1D231 and 1D250 for ATE & LER respectively were recorded. The calibration curve for derivative spectrophotometry were constructed by plotting the drug concentration versus the absorbance values of the first derivative spectrum 1D at 1D 231 and 1D250 for ATE & LER , respectively.

1.3.7 Inter-day & Intra-day accuracy & precision

A QC standard & prepared binary mixture was evaluated for Inter-day & Intraday

accuracy & precision. Accuracy was determined as the absolute value of

the ratio of the back calculated mean values of QC to their respective nominal

values & was expressed as percentage. Precision of assay was expressed as

percentage coefficient of variation (% CV) for QC sample & Binary Mixture

1.3.8 Assay of Pharmaceutical dosage form

A total number of 20 tablets (Alfusin D) accurately weighed and

powdered in a mortar. Quantities of the powdered tablets equivalent to 10 mg of Alfuzosin HCl & 0.5 mg of Dutasteride were accurately weighed and transferred in to 100 ml volumetric flask. Weighed powder was dissolved in 80:20 V/V (MeOH:H2O) mixed thoroughly and kept under mechanical shaking for 15 minutes. Solution obtain was filtered through filter paper and diluted with same solvent to get the concentration within linearity and used for the measurement of derivative spectra. The concentration of Alfuzosin HCl and Dutasteride in tablet were calculated from corresponding calibration curve.

1.4 RESULTS AND DISCUSSION

1.4.1 Development of First derivative zero crossing method

Derivative spectroscopy on the basis of zero crossing measurement involves measurement of absolute value of total derivative spectrum at an abscissa

value corresponding to the zero crossing wavelengths of the derivative spectra

of individual components. Which should be the function of the concentration of

other component Zero crossing points for ATE & LER were found to be 211.9,

225.4, 250, 275.2, 292.2 & 218.4, 231, 240.7, 310.9, 362.7 nm respectively the

measurement at 250 & 231 exhibit best linear response. So ATE was

determined by measurement of its 1D amplitude at ZCP of LER (at 231 nm ).

LER was determined by measurement of its 1D amplitude at ZCP of ATE (at

250 nm).

1.4.2 Validation23-25

1.4.2.1 Linearity

Since beer law obeys between absorbance values 0.1-1, the linearity is

established by plotting points between these two readings in triplicate. for

Lercanidipine HCl linearity found to be between 3 μg/mL to 24 μg/mL with

typical regression equation of 0.0015x-0.0003 with regression coefficient of

0.9967 & for Atenolol Linearity found to be between 3 μg/ml to 30 μg/ml with

regression equation 0.0025x+0.0005 with regression coefficient of 0.9996.

1.4.2.2 Accuracy

The accuracy of method was established in triplicate in three consecutive days. At 80%, 100% & 120% of the expected sample concentration & in synthetic binary mixture, the method found to be very accurate with recovery

1. M. VAMSI KRISHNA* and D. GOWRI SANKAR Optimization and Validation of Quantitative Spectrophotometric Methods for the Determination of Alfuzosin in Pharmaceutical Formulations ISSN: 0973-4945; CODEN ECJHAO E-Journal of Chemistry

2. Safwan Ashour, M. Fawaz Chehna, Roula Bayram Spectrophotometric Determination of Alfuzosin HCl in Pharmaceutical Formulations with some Sulphonephthalein Dyes International journal of Biomedical science

3. M. SUGUMARAN Extractive Spectrophotometric Determination of Alfuzosin from Its Bulk and Pharmaceutical Dosage Form J. Ind. Council Chem. Vol. 26, No. 1, 2009, pp. 47-49

4. SYEDA HUMAIRA, AKALANKA DEY1, S APPALA RAJU, SYED SANAULLAH Applications Of Colorimetric Methods For The Determination Of Cinitapride Hydrogen Tartarate In Drug Formulations International Journal of Pharmacy and Pharmaceutical Sciences Vol 2, Suppl 1, 2010

5. Md Ruhul Amin, Moynul Hasan, Abdullah Al Masud, Md Hanif uddin,

Md Hasanuzzaman and Mohammad Kaisarul Islam Validated Uv Spectrophotometric Method For Estimation Of Dutasteride In Tablet Dosage Form Islam M K et al. / Pharmacie Globale (IJCP) 2011, 4 (04)

6. Kamila M. M., Mondal N Ghosh L.K A Validated Spectrophotometric Method For

Determination Of Dutasteride In Bulk Drug And Pharmaceutical Formulations International Journal of PharmTech Research CODEN (USA): IJPRIF ISSN : 0974-4304

7. Vishnu P. Choudhari*, Sacchidanand R. Gite, Rahul P. Raut, Asawaree A. Hable, Sanket R. Parekar, Bhanudas S. Kuchekar Spectrophotometric Simultaneous Determination Of Dutasteride And Tamsulosin In Combined Tablet Dosage Form By First Order Derivative Spectroscopy And Area Under Curve (Auc) Spectrophotometric Methods And Its Application To Uniformity Of Content In Tablet And Capsule ISSN 0976 -044 x Volume 2, Issue 2, May - June 2010; Article 013