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  3. Investigating the increase of simvastatin drug solubility using solid dispersion method

Investigating the increase of simvastatin drug solubility using solid dispersion method

Number of pages: 144 File Format: word File Code: 32005
Year: 2016 University Degree: Master's degree Category: Medical Sciences
Tags/Keywords: evaporation - halal - Increased solubility - Increased solubility - liquidation reform - Low soluble drugs - melting method - Polyethylene glycol - simvastatin - Solid dispersion - tween
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  • Summary of Investigating the increase of simvastatin drug solubility using solid dispersion method

    Dissertation

    To receive the degree of Doctor of Pharmacy

    Persian Summary

    Simvastatin with the brand name Zocor is a drug that is widely used in the treatment of hypercholesterolemia. Simvastatin has a low solubility in water, which reduces its therapeutic benefit,

    The solubility behavior of drugs remains one of the challenging aspects in the development of formulations.

    Given that many drugs have low solubility and dissolution in water, and as a result, lower absorption and less bioavailability, various techniques are used to improve their dissolution. It has been proposed such as: micronization, solid dispersions, liquid-solid technique, microencapsulation, the use of surfactants, the use of cyclodextrins, the use of solvents

    Solid dispersion means the dispersion of one or more substances in an inert carrier or matrix.

    In this study, simvastatin solid dispersions using From various carriers, including beta-cyclodextrin, mannitol, PVPK30, PEG 400, 1000, 4000, 6000, Compritol, Glucire, HPMC6cps, HPMC15cps and Tween 20,40,60,80 with different ratios (0:1:1, 0.5:1, 1:1, 2:1, 5:1) by melting, evaporation methods. Solvent, physical mixing were made. The prepared formulations were compared in terms of saturation solubility and the selected formulations from each group were considered for further tests. In the statistical analysis of all formulations compared to pure simvastatin, the saturated solubility increased significantly. The selected formulations included: A7, B10, C7, D1, E4, F6.

    Also, the dissolution speed and flowability and compressibility of the selected formulations were studied. Formulation B10 was recognized as the superior formulation due to saturation solubility and dissolution rate and was analyzed by DSC and FTIR to check the lack of drug-carrier interference.

    In general, it can be acknowledged that the use of solid dispersion method is a suitable technique to improve the dissolution rate of simvastatin and the use of appropriate carriers can have a positive effect in this direction.

    Key words: solid dispersion, simvastatin, increasing solubility, melting method, solvent evaporation method, lipids, sugars, tweens, polyethylene glycol

    Chapter One:

    General

    1-1 - Statement of the problem And the importance of the subject

    The first condition for creating a therapeutic effect is to create appropriate bioavailability. For this purpose, the drug must be able to dissolve well in the body. Therefore, the process of dissolution can be considered as one of the main stages of achieving a therapeutic effect. The dissolution rate is a factor that represents the drug's solubility. Approximately 40% of the drugs that are used in the treatment of diseases are drugs that are poorly soluble in water (1). The low water solubility or the drug's dissolution rate, despite the proper permeability, will lead to a low concentration of the dissolved drug at the absorption site and as a result, its low bioavailability (2). Amidon and his colleagues placed this class of drugs in the category of BCS ?? compounds (3). Increasing the water solubility or dissolution rate of these compounds is one of the main problems in the development of their pharmaceutical forms. The most important way to improve dissolution is to increase the accessible surface for dissolution. To increase this level, the particle size of solid compounds can be reduced or the level of wetness can be increased. Reducing the particle size of compounds by grinding the drug powder theoretically increases the surface area available for dissolution. But in most cases, mechanized powders tend to stick together. Therefore, the use of grinding to reduce the size of particles is prohibited. One of the ways that can increase drug solubility is the use of water-soluble carriers in the form of solid dispersion. In these systems, drugs with increased solubility can be obtained by placing the drug in the base of the polymer substrate, or excipients with desirable properties (to improve the solubility of the drug) (4).Although various reports on the use of solid dispersion systems have been published, only a few commercial products have been used in the development. The cause of this problem is the possibility of physical instability of the drug enclosed in the polymer substrate (5). Separation of phases, crystal growth or transformation of material from amorphous state to crystal leads to decrease in solubility and dissolution rate. The presence of a polymer carrier in these systems is a factor that may prevent the recrystallization of the drug (6,7). Creating an amorphous state in solid dispersion formulations is an important factor in increasing its dissolution rate and preventing its crystallization is very important to maintain and stabilize the drug release process from the powder bed (8). In this research, an attempt has been made to increase its dissolution rate by preparing solid dispersions of the poorly soluble drug simvastatin using different carriers and different ratios of the drug to the carrier, and achieve the most suitable system that can improve the other physicochemical properties of the drug simvastatin in addition to improving the solubility of the drug.

    1-2-Objectives:

    Main objectives :

    Examination of various parameters related to the formulation in solid dispersion systems in order to improve the solubility of simvastatin drug

    Sub-objectives:

    A- Complete investigation of the physicochemical properties and especially the solubility of simvastatin drug

    B- Making solid dispersions of the drug Simvastatin using various auxiliary materials or changes in different manufacturing parameters

    c- Evaluation of the physicochemical properties of the prepared solid dispersion and also the solubility of simvastatin drug

    d- Obtaining the most important systems that are able to improve other physicochemical properties of simvastatin drug in addition to improving the solubility of the drug.

     

     

    Chapter Two:

    Examining the texts and studies of others

     

    Part I:

    General information about drugs Solution and methods of increasing solubility style="direction: rtl;"> 

     

     

     

     

    2-1-1- Dissolution and absorption of medicine

    The first step in drug absorption is dissolution Drug absorption is at the site of drug absorption. For example, a drug that is administered orally (tablet or capsule form) will not be able to absorb the drug particles in the digestive tract before the dissolution process and thus create a therapeutic effect. The acidity or alkalinity of the environment affects the solubility of the drug. Therefore, the place of absorption of drugs will be in the stomach and intestine. The process in which drug particles dissolve is called dissolution. During the dissolution process, drug molecules enter the solution on the surface of the first particle and create a saturated layer of drug solution that surrounds the surface of solid drug particles. This layer is called the diffusion layer. Drug molecules pass through this diffusion layer, then contact the biological membrane, and are absorbed. In the case of fast-dissolving drugs and medicinal solutions, the rate of absorption depends on the ability of the drug to pass through the biological membrane. organ delivery. The solubility behavior of drugs remains one of the most challenging aspects in formulation development

  • Contents & References of Investigating the increase of simvastatin drug solubility using solid dispersion method

    List:

    Title

    Page Title

    Persian Summary. 1

    Chapter One: Generalities

    1-1 - Statement of the issue and the importance of the issue. 3

    1-2-Objectives: 4

    Chapter Two: Reviewing the texts and studies of others

    Part One: General information about poorly soluble drugs and methods of increasing solubility

    2-1-1-Dissolution and absorption of drugs. 7

    2-1-2- Liquidation. 9

    2-1-3- Dissolution theories. 9

    2-1-4- dissolution speed. 10

    2-1-5- Classification of drugs from the point of view of solubility and permeability. 11

    2-1-6- methods of increasing solubility. 13

    2-1-6-1- Use of solvents 13

    2-1-6-2- Use of surfactants 14

    2-1-6-3- Use of cyclodextrins: 14

    2-1-6-4- pH adjustment: 15

    2-1-6-8-4- Disadvantages of dispersions solid. 26

    2-1-6-8-5- The future of solid dispersions. 27

    2-1-6-8-6- Evaluating the efficiency of solid dispersions in in vitro conditions. 27

    2-1-6-8-7- Choosing the right carrier for solid dispersion. 28

    2-1-7- Materials used. 28

    2-1-7-1- sodium lauryl sulfate. 28

    2-1-7-2-Polyethylene Glycol (PEG): 30

    2-1-7-3-Ethanol: 33

    2-1-7-4-Polyvinyl Pyrrolidine ((PVP: 33

    2-1-7-5-Hydroxypropyl Methyl Cellulose (HPMC)) 35

    2-1-7-6- Glyceryl behenate: 37

    2-1-7-7- Avicel 102pH (microcrystalline cellulose): 38

    2-1-7-8-: Gelucire 43/01. 39

    2-1-7-9- Polysorbates: 40

    2-1-7-magnesium stearate: 41 2-1-7-mannitol

    2-2-Mechanism of action: 47

    2-2-3- Other cardioprotective effects of statins: 48

    2-2-4- Statins and endothelial function: 48

    2-2-5- Statins and plaque stability: 48

    2-2-6- Other effects of statins: 49

    2-2-7- The toxicity of statins: 2-2-8- Simvastatin. 51- Physicochemical properties of simvastatin. 52- 2-8-3- Pharmacokinetics

    2-2-8-4- side effects. 53

    2-2-8-5- Cases and dosage. 54

    2-2-8-6- Precautions and contraindications. 54

    2-2-8-7- Medicinal forms: 54

    Part three: review of some articles and studies of others in this field

    2-3-1 review of some studies of others. 56

    Chapter Three: Materials and Methods

    3-1-Introduction. 60

    3-1- Devices: 61

    3-2- Materials. 62

    3-3- Pre-formulation studies. 62

    3-4- Manufacturing methods of simvastatin solid dispersion formulations. 65

    3-4-1- Construction of simvastatin solid dispersion systems of group A formulations. 65

    3-4-2- Construction of simvastatin solid dispersion systems of group B formulations. 66

    3-4-3- Construction of solid dispersion systems of simvastatin group C formulations. 67

    3-4-4- Construction of solid dispersion systems of simvastatin group D formulation. 67

    3-4-5- Construction of solid dispersion systems of simvastatin group E formulation. 68

    3-4-6- Fabrication of solid dispersion systems of simvastatin group F formulation. 69

    3-5-Control tests of prepared solid dispersion formulations 70

    3-5-1-Saturation solubility. 70

    3-5-2- Statistical study of saturated solubility in order to select superior formulations. 70

    3-6- Additional tests on selected formulations. 70

    3-6-1- Determining the amount of the active ingredient of the tablet prepared from the selected formulations. 71

    3-6-2- Dissolution speed test on selected formulations. 71

    3-6-3- Examining the similarity between the selected formulations. 71

    3-6-4- Flowability study of selected formulations. 71

    3-6-5- Determining the saturation solubility of physical mixing of superior formulations. 72

    3-6-6- Flowability study of physical mixing of selected formulations. 72

    3-6-7- Examining the FTIR spectra of superior formulations. 72

    3-6-8-72

    3-6-8- Examining the diagrams obtained from DSC of superior formulation. 73

    Chapter Four: Results

    4-1- The results of pre-formulation studies. 75

    4-2- The results of control tests of prepared solid dispersion formulations 80

    4-2-1. Results from saturation solubility. 80

    4-2-2. Investigation of statistical studies of saturated solubility in order to select superior formulations. 85

    4-3- Additional tests on selected formulations. 93

    4-3-1- Determining the amount of the active ingredient of the tablet prepared from the selected formulations. 93

    4-3-2- Dissolution speed test on selected formulations. 93

    4-3-3- Examining the similarity between selected formulations. 102

    4-3-4- Results of study of flowability and compressibility of selected formulations. 102

    4-3-5- Results of saturation solubility of physical mixing of selected formulations. 103

    4-3-6- The results of the study of flowability and compressibility of physical mixing of selected formulations. 103

    4-3-7- The spectra obtained from FTIR spectroscopy of the superior formulation (B10) 104

    4-3-8- The diagrams obtained from DSC of the superior formulation (B10) 106

    Chapter five: Discussion and conclusion

    5-1- Introduction. 110

    5-2- Examining the results of statistical studies on the saturation solubility of the prepared formulations in order to select the selected formulations. 110

    5-3- Examining additional tests on selected formulations. 116

    5-3-1- Examining the results of determining the amount of the active ingredient in the tablets prepared from the selected formulations. 116

    5-3-2- Examining the results of the dissolution rate test of tablets prepared from selected formulations. 116

    5-3-3- Examining the results of flowability and compressibility studies of selected formulations. 117

    5-3-4- Examining the saturation solubility results of physical mixing of selected formulations. 118

    5-3-5- Examining the results of flowability and compressibility studies of physical mixing of selected formulations. 118

    5-4- Choosing the best formula and additional studies on it. 119

    5-4- 1- Analysis of spectra obtained from FTIR spectroscopy of the superior formulation. 119

    5-4-2- Analysis of diagrams obtained from DSC of the superior formulation. 119

    5-8- General conclusion. 120

    5-9- Suggestions. 121

     

    English summary. 122

    Resources. 124

     

     

    Source:

    1- Ohahia T., Kitamura S., Kitagava M., Terada K. Dissolution mechanism of poorly water soluble drug from extended release solid dispersion system with ethylecellulose and hydroxypropylmethyl cellulose. Int. J. Pharm. 2005; 302:95-102

    2- Leuner C., Dressman JB. Improving drug solubility for oral delivery using solid dispersions.  Eure. J. pharm. Sci. 2000; 50:47-60

    3- Amidon GL., Lenneras H., shah VP., Crison JR. A theoretical basis for a biopharmaceutical drug classification, the correlation for in vitro drug product dissolution and in vivo bioavailability. Pharm. Res. 1955; 12: 413-420

    4- Chiou WL., Riegelan S. Pharmaceutical applications of solid dispersion systems. J. pharm. Sci. 1971; 60: 1281-1302

    5-Serajuddin A.T.M Solid dispersion of poor water-soluble drugs: early promises, subsequent problems and recent breakthroughs. J, pharm. Sci. 1999;88:1058-1066

    6-Motsumoto T., Zografi G. Physical properties of solid molecule dispersions of imdomethacin with PVP VA in relation to indomethacin crystallization. Pharm. Res. 1999; 16:1722-1728

    7-Van den Mooter G, [et al]. Physical stabilization of amorphous ketoconazole in solid dispersion with polyvinylpyrrolidone k25. Eur. J. pharm. Sci. 2001; 12:261-269

    8- Isoherranen N., Kunze K.L., Aleen K.E., Nelson W.L., Tunmel K.E. Role of Itraconazol metabolites in CYP3A4 inhibition. Drug metabolite disposition. 2004; 32:1121-1131

    9- Allen L.V., Popovich NG., Ancel H.C. Ansel's pharmaceutical dosage forms and drug delivery system. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2005. Pp 148,166-7

    10- Rafiei Tehrani, Morteza. pill making Tehran: University of Tehran; 1377. pp. 21-9, 416-415

    11- The united state pharmacopeia. 31st rev. Rockville; 2008. Vol 1. P268-270

    12- Rafiei Tehrani, Morteza. pill making

Investigating the increase of simvastatin drug solubility using solid dispersion method
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