Modulation and Assessment of Controlled Released Matrix Tablet of Losartan Potassium

Wissenschaftliche Studie, 2012

104 Seiten



1 Introduction
1.1 Oral Controlled Drug Delivery System
1.2 Advantage and Disadvantage of Oral Controlled Drug Delivery system
1.2.1 Advantages of Oral Controlled Drug Delivery System
1.2.2 Disadvantages of Oral Controlled Drug Delivery System
1.3 Classification of controlled drug delivery system
1.4 Factors influencing the design of controlled drug delivery system
1.4.1 Physicochemical properties Aqueous solubility Partition coefficient Drug stability Protein binding Molecular size and diffusivity
1.4.2 Biological properties Absorption Distribution Metabolism Duration of Action Side effects Margin of safety
1.5 Drug Selection for Oral Controlled Drug Delivery System
1.6 Basic Kinetics of Controlled Drug Delivery
1.7 Types of Oral Controlled Release Systems
1.7.1 Coated Pellets or Granules
1.7.2 Microencapsulation
1.7.3 Ion-Exchange Resin
1.7.4 Osmotic Systems
1.7.5 Monolithic matrix Advantages of matrix systems Disadvantages of the matrix systems
1.8 Mechanisms of drug release from matrix systems
1.8.1 Diffusion- controlled systems
1.8.2 Water Penetration-Controlled Systems
1.8.3 Erosion-Controlled Systems
1.9 Mode of release from hydrophilic matrix dosage form
1.10 Matrix type tablet
1.11 Research Envisaged
1.12 Drug Profile
1.12.1 Losartan Potassium
1.12.2 Methocel K100M Premium CR EP
1.12.3 Kollidon ® SR
1.12.4 Eudragit RSPO

2. Review of Literature

3. Aim and Objectives

4. Plan of work

5. Development of Formulation
5.1 Preformulation Studies
5.1.1 Analysis of Losartan potassium
5.1.2 Organoleptic Properties and Description
5.1.3 Melting Point
5.1.4 Evaluation of Powder Angle of Repose Bulk density Carr’s Index Husner’s Ratio
5.1.5 Solubility
5.1.6 Spectroscopy
5.2 Material
5.3 Preparation of matrix tablets
5.4 Evaluation of Developed formulation
5.4.1 Physical Evaluation of Developed Formulations

6. Result and Discussion
6.1 Preformulation Studies for Losartan potassium
6.2 Evaluation of Developed Formulations

7. Summary and Conclusion

8. Reference

9. Appendices
A List of Abbreviations
В List of Equipments/Instruments
C List of Chemicals
D List of Published Papers
E List of Papers Presented


I take this privilege and pleasure to acknowledge the contributions of many individuals who have been inspirational and supportive throughout my work undertaken and endowed me with the most precious knowledge to see success in my endeavor. My work bears the imprint of all those people I am grateful to.

With great pleasure and profound sense of gratitude, I consider myself most lucky to work under the esteemed guidance of respected Dr. Dheeraj T. Baviskar, Director/Principal, Institute of Pharmaceutical Education, Boradi, for his valuable guidance, keen interest, inspiration, unflinching encouragement and moral support throughout my dissertation work. His strict, discipline, urge for hard work, principle, simplicity and provision of fearless work environment will cherish me in all walks of life. I also heartily congratulate him for his publication of the three books.

I wish to express my thanks to Hon. Tusharbhau V. Randhe. President Kisan Vidya Prasarak Sanstha, Shirpur for providing necessary facilities to perform the project work.

I am immensely thankful to Mr. Anup M. Akarte, Vice-principal Institute of Pharmaceutical Education, Boradi, for providing all the necessary facilities to carry out this work.

It is my privilege and honor to extend my gratitude to Mr. Mangesh K. Sapate, Mr. Pankaj S. Patii, Mr. Amarjit P. Rajput, Mr. Sachin M. Mahajan for their valuable guidance and useful suggestions during the progress of my study.

I shall extend my gratitude to Dr. D.K. Jain Sir, Principal, College of Pharmacy, I.P.S. Academy, Indore, for his guidance, encouragement and support during my academics studies and rendered to complete dissertation successfully.

I am also thankful to Mr. Mahesh P. Pawar HOD, M.A.H. College of Pharmacy, Boradi and Mr. Dynoba R. Rathod for their valuable guidance and throughout the work.

It is with deep gratitude and humbleness, I express my indebtedness to Mr. Ramakrishna Prasad (Technical Assistant Dr.Reddy's Laboratories Hyderabadjndia), Miss. Suneeta Sonawane(Technical Assistant,BASF, India), Mr. Suvarnaraj Borkar (Material Planning Co- ordinator, Colorcon Asia Pvt. Ltd., Goa), Mr. Dattatray Niwatkar (Technical Services Lab Manager, Colorcon Asia Pvt. Ltd., Goa), Miss. Shilpa Phadte (Technical Services Lab Manager, Colorcon Asia Pvt. Ltd., Goa) for providing necessary polymers and excipients as a gift sample which were necessary to carry out my project work.

I also owe my sincere thanks to senior research scholars Amritkar Amol S, Bare Kapil R, Biranwar Yogeshkumar A, Chaudhari Hiralal S, Gawale Chandrakant S, Kale Mangesh T, Kale Sachin S, Lohar Mahadev S, Mahajan Vaishali R, Maniyar Ajim H, Narkhede Deepak Ashok, Parik Venkatesh B, Patil Rahul M, Patil Satish K, Salunke Hemant D, Saste Viraj S, Wagh Kalpesh S for their valuable suggestions, ever willing help and moral support during my dissertation work.

I express my thanks to my seniors Rohan Desale, Ronak Patel, Smita Mali, Kalyani Sonawane, Bhavana Patil and Bhima Pawar for the kind support.

I express my sincere thanks to all teaching and non-teaching staff members, especially Mukesh bhau, Kailasbhau, Nandu Sir, etc. for their timely help and co-operation during my thesis work. I also express my sincere thanks to

Pradipbhausaheb Librarian Institute of Pharmaceutical Education, Boradi, for providing valuable books beyond due dates.

".'Friends are in need are friends indeed”, I am really thankful to batch mates Vishal Bhamare, Praful Parihar, Shivaji Garde, Tosif Khatik, Arvind Hatkar, Dnyaneshwar Halor, Rushab Patel, Chandrakant Patel, Pankaj Behere, Rahul Baviskar, Harshal Chavhan , Shilpa Joshi, Charulata Padavi, Devarshi Patel and Poonam Shimpi for their invaluable suggestions, constant encouragement, moral support throughout my dissertation work and comfortable stay in Boradi.

How can I forget to convey my heartfelt thanks to my seniors Sharda Bagal, Borse Jayshree, Harshal Gahiwade, Yogita Nikum, Sagar Shimpi, Swati Dhawale, Dipika Patil, Dipal Patel, Anjana Patel, Nikita Panchal, Unnati Pandya, Pankaj Metkar, Amar Deshmukh, Tushar Patel, Sagar Sangle and Chaten Joshi who are always behind me to support and encourage me throughout the course of my study.

I also express my thanks to my juniors Chandranil Ishi, Renuka Amuratkar, Pooja Danej, Bhagyashree Salunke, Mahesh Sonar, Chetan Patil, Savita Ghule andShital Suryawanshi for their help and co-operation.

I often wonder, if one gets to see God in the moral life they might be like my beloved Father Shri. Kailas Hari Khairnar and beloved Mother Smt. Sadhana Kailas Khairnar who showers their best fortunes always on me. From the deepest depth of my heart to express my thanks, I bow my head to the feets of my beloved parents whose uncompromising life principles, love, affection, has been always unshared and showered upon me at all stages of life and giving me more than what I deserved in my life.

Grandparents are like an old shady tree lovingly showering their cool shade to the grandchildren. Through every stage, we learn new things and gain wisdom and knowledge. As we learn more, we know ourselves more and the world as we know it. This wisdom needs to be passed on to future generation, and this is why grandparents are so important. Giving children roots in the past and the present gives children a sense of unity and belonging. I take this opportunity to thanks Aaji and Aappa to shape my knowledge of wisdom and to make me morally strong. Grandparents are certainly treasures of love and wisdom who enrich our life manifold!

I am grateful and thankful to my loving brother, Sumit who always kept me under shade of his affection and given me inspiration, encouragement and emotional support throughout my life. I also share my happiness and credit with my fiancé Harshada(Priti) for give love and her kind support for completion of my project work.

At last but not the least I am very much grateful to the Almighty who gave strength, courage and critical situations of my life and created this beautiful universe.

Amit Kailas Khairnar

(B.Pharm. final year)


1. Parameter for drug selection

2. Pharmacokinetic parameter for drug selection

3. Coating materials used in Microencapsulation process

4. Evaluation of physical properties of powder blend of all formulation

5. Solubility of Losartan potassium in different solvents

6. Wavelength of maximum absorbance (λ max) in different solvente

7. Beer-Lambert’s plot in water 0.1 N HCl and pH 6.8 buffer for Losartan potassium

8. Composition of controlled released matrix tablet of losartan potassium

9. Evaluation of different formulations of Losartan potassium

10. Mean (± S.D.) percent cumulative drug released from formulations of Losartan potassium


1. Drug level versus time profiles showing the relationship between (A) Controlled release; (B) Prolonged release and (C) conventional release drug delivery system.

2. Drug Mechanism (ADME)

3. Release of the drug in conventional system

4. Release of the drug in controlled release system

5. Schematic illustration of the mechanism of drug release from a diffusion based matrix tablet (t= time)

6. Schematic representation of a matrix release system

7. A typical diagram showing the water penetrating controlled drug delivery

8. Release Process for Controlled Release tablet

9. Mode of action of hydrophilic matrix dosage form

10. Various types of dosage forms with Matrix tablet

11. Mechanism of Action of Losartan Potassium

12. FTIR-spectra of HPMC K100M CR

13. FTIR-spectra of Kollidon® SR

14. Spectrum of Losartan potassium in 0.1 N HCl

15. Spectrum of Losartan potassium in pH 6.8 phosphate buffer

16. FTIR spectrum of Losartan potassium

17. Beers-Lamberts plot of Losartan potassium in 0.1 N HCl

18. Beers-Lamberts plot of Losartan potassium in 6.8 buffers

19. Release profile of Losartan potassium + HPMC K100

20. Release profile of Losartan potassium + Kollidon SR

21. Release profile of Losartan potassium + Eudragit RSPO


Ideally, a drug should arrive rapidly at the site of action (receptor) in the optimum concentration, remain for the desired time, be excluded from other sites, and be rapidly removed when the goal is achieved. Generally, the time course of a dosage form (pharmacokinetics) in man is considered to be controlled by the chemical structure of the drug. Decreasing the rate of absorption and/or changing the dosage form provide a useful adjunct. When it is not feasible or desirable to modify the drug compound on a molecular level, often sought is a product that will require less frequent administration to obtain the required biological activity time profile. It may be desirable to decrease the absorption rate in order to obtain a more acceptable clinical response. The goal of designing sustained release matrix delivery systems is to reduce frequency of dosing or to increase the effectiveness of the drug by localizing at the site of action, reducing the dose required, or providing uniform drug delivery.

Hence, designing a sustained release formulation for an antihypertensive drug may prolong therapeutic concentration of drug in the blood and decrease the frequency of dosing and also improve the patient compliance. So in the present study, attempts will be made to formulate a sustained release matrix tablets containing an antihypertensive drug.

In December 1843, a patent was granted to the Englishman, William Brockedon for a machine to compress powders to form compacts. This very simple device consisted essentially a hole (or die) bored through which the powder was compressed between the two cylindrical punches; one was inserted into the base of die and at a fixed depth, the other was inserted at the top of die and struck with hammer. The invention was first used to produce compacts of potassium bicarbonate and caught the imagination of no. of pharmaceutical companies. Later, welcome in Britain was the first company to use the term “tablet” to describe the compressed dosage form.1

Oral route has been the commonly adopted and most convenient route for the drug delivery. Drug delivery design depends on various factors such as type of delivery system, the disease being treated and the patient, the length of the therapy and the properties of the drug.2 A sizable portion of orally administered dosage forms, so called conventional, are designed to achieve maximal drug bioavailability by maximizing the rate and extent of absorption. With such dosage forms have been useful, frequent daily administration is necessary, particularly when the drug has a short biological half life. This may result in wide fluctuation in peak and trough steady-state drug levels, which is undesirable for drugs with marginal therapeutic indices. Moreover, patient compliance is likely to be poor when patients need to take their medication three to four times daily on chronic basis. Fortunately, these shortcomings have been circumvented with the introduction of controlled release dosage forms.3

1.1 Oral Controlled Drug Delivery System

Sustained release(SR), sustained action, prolonged action, controlled release(CR), extended action, timed release, depot and repository dosage forms are terms used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose4. The term “controlled release” has become associated with those systems from which therapeutic agents may be automatically delivered at predefined rate over long period of time.5 There are also good commercial reasons for continuously increasing trend towards sustained release system. In the next few years, drug patents on the majority of today’s most used drugs will expired. Formulations of these drugs in controlled release system are one mean to extend the proprietary protection against generic products, particularly if the controlled release drug delivery system is patented. These are the market-driven factors and others are the patient-related factors such as therapeutic advantage, reduction in adverse side effect, patient comfort and reduction in healthcare cost. But, the success of any technology relies on the ease of manufacturing process and its reproducibility of desirable biopharmaceutical properties. There are number of major deficiencies of conventional dosage forms, few of which are listed below.6

1. Inconvenience and /or difficult use of drugs with very short duration of action or biological half-life
2. Need of frequent dosing
3. Potential for “peak- valley” plasma levels, leading to toxicity and side effect and incomplete therapy
4. Poor patient compliance, due to adverse effects, forgetfulness and inconvenience of dosage forms
5. Frequently needed for large systemic concentrations in order to achieve adequate concentration at target site or action
6. Potential variations in oral absorption due to variation in GIT pH profile, presence and type of food and transit time in gut

Controlled release also denotes system which can provide some control whether this is of a temporal or spatial nature or both for drug release in the body.7 Sustained release system include any drug delivery system that achieves slow release of drug over an extended period of time. Sustained release dosage forms cover a wide range of prolonged action preparations that provides continuous release of their active ingredients for a specific period of time. By prescribing sustained release systems, it is possible to achieve several desirable therapeutic advantages.8

If the system is successful in maintaining constant drug levels in the blood or target tissue, it is considered as a controlled-release system. If it is unsuccessful at this but nevertheless extends the duration of action over that achieved by conventional delivery, it is considered as a prolonged release system. This is illustrated in the following figure no. I.9

Abbildung in dieser Leseprobe nicht enthalten

Figure 1: Drug level versus time profiles showing the relationship between (A) Controlled release; (B) Prolonged release and (C) conventional release drug delivery system.

In contrast to the above, controlled drug delivery is aimed at providing not only sustained action, but also constant, that is ideally zero-order release rate in which the amount of drug released to the absorption site remains reasonably constant over prolonged periods of time.10 The controlled release dosage forms (CDDS) are based on low but constant drug release for extended period of time CDDS provide continuous release of drug at a predetermined rate for predetermine time.11 The frequency of administration or the dosing interval of any drug depends upon its half-life or Mean Residence Time (MTR) and its Therapeutic Index (TI).12 14,15,16,17

1.2 Advantage and Disadvantage of Oral Controlled Drug Delivery System

1.2.1 Advantages of Oral Controlled Drug Delivery System

1. The frequency of drug administration is reduced.

2. Patient compliance can be improved.

3. Drug administration can be made more convenient as well.

4. The blood level oscillation characteristic of multiple dosing of conventional dosage form is reduced.

5. Better control of drug absorption can be attained, since the high blood level peaks that may be observed after administration of a dose of a high availability drug can be reduced.

6. The characteristic blood level variations due to multiple dosing of conventional dosage forms can be reduced.

7. The total amount of drug administered can be reduced, thus:
i. Maximizing availability with minimum dose;
ii. Minimizing or eliminate local side effects;
iii. Minimizing or eliminate systemic side effect;
iv. Minimizing drug accumulation with chronic dosing.

8. Safety margin of high potency drugs can be increased and the incidence of both local and systemic adverse side effects can be reduced in sensitive patients.

9. Improve efficiency in treatment.
i. Cure or control condition more promptly;
ii. Improve bioavailability of some drugs;
iii. Make use of special effects; e.g. controlled release morning relief of arthritis by dosing before bedtime.

10. Controlled release provide a uniform concentration or amount of the absorption site and thus, after absorption, allow maintenance concentrations within a therapeutic range, which minimized side effects and also reduces the frequency of administration.

11. Controlled release products are the formulations that release active drug compounds into the body gradually and predictably over a 12 to 24 hours period and that can be taken once or twice a day.

12. Predictable and reproducible release rates for extended duration.

13. Maintenance of optimum therapeutic drug concentration in the blood with minimum fluctuations.

14. Delivery of drug in the vicinity of site of action.

15. More efficient utilization of active agent.

16. Improve in patient compliance.

17. Greater selectivity of pharmacological activity.

18. Reduction in GI irritation and other dose-related side effects.

19. Enhanced bioavailability.

20. Greater effectiveness in chronic conditions.

21. Economy.

22. Enhancement of duration of action for drugs with short half-life.

1.2.2 Disadvantage of Oral Controlled Drug Delivery system [18],[19]

1. Administration of controlled release medication does not permit the prompt termination of therapy.

2. Flexibility in adjustment of dosage regimen is limited.


1. Jain N. К. pharmaceutical Product development BS Publication 2006: 61.

2. Pandya .S. “Formulation and Evaluation of controlled release matrix tablet of Glipizide”. 2006; 1-3.

3. Rahamathullah .S. “Design and Evaluation of controlled release layered matrix tablet of Paracetamol and Verapamil HCl”. University of Malaysia. 2009; 1-2.

4. Lachmann L, Lieberman HA, Kanig JL. The Theory & Practice of Industrial Pharmacy, 3rd Ed. Varghese Publishing House, Bombay 1991: 416-453.

5. Chavhan S. S., “Studies On Once Daily Sustained Release Formulation Of Nicorandil” thesis submitted at Pune University. 2008.

6. Gennaro AR, Remington: The Science and Practice of Pharmacy, 20th Ed., Mack publishing house, Easton Pannsylvania.2000; 903-914.

7. Robinson J.R., Lee V.H. (Ed). Controlled Drug Delivery: Fundamental & Applications. 2nd Ed. Marcel Dekker Inc., New York. 1987; 373.

8. Cherng-ju Kim. Controlled Release Dosage Form Design. Culinary and Hospitality Industry Publications Services, florida.2000; 3-4.

9. Gennaro A.R. (Ed.) Remington. The Science & Practice of Pharmacy. 19th Ed. Vol. II; 1995: 1662.

10. Zaffaroni A., Applications of polymers in rate-controlled drug delivery in biomedical and dental applications of polymers. Gebelein C.G. and Koblitz F.F., Eds., Plenum Press. New York. 1981: 293.

11. Kulkarni J.S., Pawar A.P., Shedbalkar V.P., Biopharmaceutics and Pharmacokinetics. CBS Publication. New Delhi. 1st Ed. 2006: 41

12. Brahmankar, D.M., Jaiswal, S.B., In; Biopharmaceutics and Pharmacokinetics A Treatise. 1st Ed., Vallabh Prakashan, Delhi, 1995, 335-357.

13. L. Maggi, U. Conti., Geomatrix Technology., Sengo and Forma, 2003

14. Gennaro A.R. (Ed.) Remington. The Science & Practice of Pharmacy. 19th Ed. Vol. II; 1995: 1662.

15. Rang H.P., Dale M.M. Ritter J.M., More P.K. Pharmacology. 6th Ed. United Kingdom: Churchill Livingston; 2006 :110-11

16. Hoffman A. Pharmacodynamics aspects of sustained release preparations. Adv. Drug Del. Rev. 1998; 33: 185-99.

17. Lachmann L, Lieberman HA, Kanig JL. The Theory & Practice of Industrial Pharmacy, 3rd Ed. Varghese Publishing House, Bombay 1991: 256.

18. Jain .N.K. Controlled and Novel Drug delivery. 1st Ed. New Delhi: CBS publishers; 2002: 54

19. Notari, R., Biopharmaceutics and Clinical Pharmacokinetics, An Introduction, 3rd Ed., Marcel Dekker Inc. New York. 1980: 152-54.

Ende der Leseprobe aus 104 Seiten


Modulation and Assessment of Controlled Released Matrix Tablet of Losartan Potassium
Institute of Pharmaceutical Education Boradi
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Losartan potassium, controlled release
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Amit Khairnar (Autor), 2012, Modulation and Assessment of Controlled Released Matrix Tablet of Losartan Potassium, München, GRIN Verlag,


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