To Enhance the Physicochemical Properties of Metoprolol Succinate By Co-Crystal Technique

 

Sachin S. Mali*,  Suresh G. Killedar

Shri Jagdishprasad Jhabarmal Tibrewala University, Jhunjhunu, Rajasthan, India

 

ABSTRACT:

Metoprolol succinate is a selective beta receptor blocker having poor physico-chemical and micromeritic properties. Therefore the co-crystals of metoprolol have been attempted to improve its physic-chemical and micromeritic characteristics. The effect of different co-formers such as benzoic acid and salicylic acid on flow ability of metoprolol by co-crystal technique. The co-crystals were characterized by Infra-red spectroscopy(I.R).It was found that micromeritic properties such as angle of repose, and physicochemical properties such as melting point. of co-crystals were significantly improved than that of pure metoprolol succinate. Hence it could be concluded that co-crystals could be one of the effective approaches for improved performance of metoprolol succinate.

 

 

INTRODUCTION:

Co-crystal can be defined as crystalline complexes of two or more neutral molecular constituents bonded together in the crystal lattice through non-covalent interaction primarily hydrogen bonding. It is versatile process to control size and type of crystals and give benefits over granulation technique in which more time. Cost and energy is consumed. It can be also be a good technique for improvement of dissolution behavior of certain drugs characterized by low solubility and dissolution rate. The formation of pharmaceutical co-crystals involves incorporation of a given API with another pharmaceutically acceptable molecule in the crystals lattice. Co-crystals can be constructed through several types of interactions. Including hydrogen bonding. p stacking, and vanderwaals forces (1) Compared to other classes of solid modification techniques employed by pharmaceuticals industries. Co-crystals is found to be an advantageous alternative for drug discovery and drug delivery

The term co-crystal is still under debate in the academic and industrial community. To date a universal and agreeable definition of a constitutes a co-crystal is unavailable. Co-crystal are defined differently by different scientist as;

 

Fig.No.1.Possible solid form of a drug substance Red, Blue, Yellow and Green represent drug, water/ solvent, counterion, and conformer molecules respectively.

Co-crystals can be defined as “a molecular complex that contains two or different molecules in the same crystal lattice ’’(2). “Multi-component solid state assemblies of two or more compounds held together by any type of combination of intermolecular interaction”(3). “crystalline material made up of two or more components, usually in a stoichiometric ratio, each component being an atom, ionoc compound and molecule”(4). “a crystalline complex of two or more neutral molecular constituents bound together in the crystal lattice through noncovalent interaction, often including hydrogen bonding”(5). “Are formed between a molecular or ionic API and a crystal formed that is a solid under ambient conditions”(6).

 

Most of the wider scientific community agrees, however that crystals are crystalline materials that contains more than one component(i.e. multi component crystals).these multi-component system are usually designed following crystal engineering principle and are often stabilized by non-covalent interactions. APIs can exist in variety of distinct solid forms, including polymorphs, solvates, hydrates, salt, crystals and amorphous solids some scientist have attempt to differentiates cocrystals form solvates or hydrate by limiting cocrystal component to solids at room temp. accordingly, if one of the component is pharmaceutically active ingredient, they are referred to as pharmaceutical cocrystals, (7). Indeed, the definition of crystals is important from a regulatory perspective as it has intellectual property implication, since cocrystals are novel useful and non-obvious,(8)

 

Methods of prepration of co Crystals:

Fig.No.2.Co-crystal Formation

 

Co-crystal are often prepared by a traditional solution crystallization approach such as solvent evaporation, cooling, or anti solvent addition. Co crystal can be prepared by solvent  and solid based methods.

Solvent based method involves

1.    Slurry conversion solvent evaporation

2.    Cooling crystallization

3.    Precipitation

4.    Solid based method involves

5.    Griding

 

Solution Co-crystallization:

There are a number of reasons for the popularity of the solution based approach. Solution crystallization can yield large, well-formed single crystals, from which one may easily evaluate crystals habit and surface features. Analysis of the diffraction pattern of a single crystal is typically the best means of obtaining an absolute crystal structure determination. Further, solution crystallization is an established and effective purification step. There are however few drawbacks of solution based approach they are solubility of the starting component is one obstacle as a suitable solvent for all ingoing material must be identified before co-crystallisation may occur.

 

The solvent employed in the cocrystallisation may possess the ability to interfere with the desired cocrystal lattice. In this way, solvate formation hampers rational cocrystal design. In this case of polymorphic cocrystal system, it could be the case that solution crystallisation leads to an undesired kinetically controlled metastable polymorph. An additional drawback to cocrystallisation from solution is the typically large volume of solvent necessary to prepare the co- crystals.

 

Slurry Conversion:

Slurry conversion experiments were conducted in different organic solvents and water solvent was added to the cocrystal former and the resulting suspension was stirred at room temperature for some day. After some days, the solvent was decanted and the solid material was dried under a flow of nitrogen for few min. The remaining solids were then characterized.

 

Anti Solvent Addition:

This is one of the methods for precipitation or recrystallisation of the co crystal former and active pharmaceutical ingredient. Solvents include buffer(pH) and organic solvents for example preparation of co crystal of aceclofenac using chitosan, in which chitosan solution was prepared by soking chitosan in glacial acetic acid. A weighed amount of they drug was dispersed in chitosan solution by using high dispersion homogenizer. This dispersion was added to distilled water or sodium citrate solution to precipitate chitosan on drug (9).

 

Solid State Cocrystallization:

Grinding:

An alternative to the solution-based approach exists in the approach of solid-state grinding. The relative solubility of ingoing components in a particular solvent is not a concern when solid state grinding is employed. There by increasing the utility of this technique over the solution approach by greatly easing the burden of expierment design. Solvent-free solid-state cocrystallisation also eliminates the possibility of forming undesired solvent. There is some evidence to indicate that, at least in single component systems, solid-state grinding leads to the hing-melting thermodynamically stable polymorph (8).

Solid-state cocrystallisation also possesses drawback. While the field of crystal engineering develops, the primary point of interest upon forming a cocrystal material is often the elucidation of its crystal structure. Single crystal X-ray diffraction (XRD), which requires a crystal of sufficient size, is incompatible with solid-state grinding, which is a particle size reduction technique. Thus, a cocrystal prepared only by solid-state grinding will require alternative, less common means of revealing structural features of interest, such as the hydrogen bond motif that may be present. Other disadvantages to solid state grinding include the lack of purification that solution crystallisation may provide, and the increase in crystalline disorder which accompanies some materials upon energetic grinding.

 

Significance of Co-crystallization:-

Pharmaceutical cocrystals represent an advantageous class of crystal from in the context of pharmaceuticals. Co-crystallization has various advantages over the other particle enlargement techniques which are as given below.

·      Very simple in comparison to other particle enlargement technique.

·      Economic in terms of processing cost.

·      Ability to generate co-crystals in a single step.

·      Less manpower requirement because one person can easily handle the whole cocrystallisation process.

·      Generate different crystalline forms of a drug, even for nonionizable drugs.

·      Modify significantly the properties,

·      Solubility

·      Dissolution rate

·      Bioavailability

·      Chemical stability

·      Moisture uptake

·      Mechanical behavior

·      Intellectual property and patents.

 

Limitation of co-crystal:

·      Use of organic solvent cannot be avoided (10).

·      Large quantity of solvent needed. (10)

 

Introduction of Metoprolol Succinate Drug:

Structure of Metoprolol:

 

 

Fig No.3.  {2-hydroxy-3-[4-(methoxyethyl)phenoxy]propyl} (propen- 2-yl) amine.

 

Metoprolol is a cardio selectiveβ1-adrenergic blocking agent used for acute myocardial infarction(MI),heart failure, angina pectoris and mild to moderate hypertentionphylaxis for migraine headaches. metoprolol is structurally similarly to bisoprolol, acebutolol and atenolol in that it has to substituent’s in the Para position of the benzenering. The beta 1-selectivity of these agents is thought to be due in part to the large substituent’s in the para position. At low doses, metoprolol selectively blocks cardiac beta1 adrenergic receptors with little activity against beta2 adregenic receptors of the lungs and vascular smooth muscle. Receptor selectivity decreases with higher doses. Unlike propanolol and pindolol, metoprololdose not exhibit membrane stabilizing and intrinsic sympathomimetic activity. Membrane-stabilizing effects are only observed at doses much higher than those needed for beta adrenergic blocking activity. Metoprolol possesses a single chiral center and is administered as racemic mixture. Metoprolol is a selective ß₁-receptor blocker medication (11). It is used to treat high blood pressure, chest pain due to poor blood flow to the heart, an a number of condition involving an abnormally fast heart rate(11). It is also used to prevent further heart problems after myocardial infarction and to prevent headache in those with migraine. (11) It is comes in the formulations that can be taken by mouth or given intravenously. The medication is often taken twice a day metoprolol may be combined with hydrochlorothiazide in a single pill.(11)

 

Metoprolol was first made in 1969(12). It is on the World Health Organization’s List of Essential Medicines, the most important medication needed in a basic health system(13). It is available as a generic drug. In 2010 metoprolol was the 14^th most prescribed medication in the united states.(14) Drug information as shown in table number 1.

 

Table No.1.Drug Information.

 

Uses :

Metoprolol succinate is used for number of conditions such as Hypertension. Angina, acute myocardial infarction, congestive heart failure and prevention of migraine headaches (10-15).

 

Adverse effect:

Side effect especially with higher doses include(16)

1.Dizziness

2.Fatigue

3.Unusual dreams

4. Diarrhea

5.Depression and vision problem

 

Precautions:

Metoprolol may worsen the symptoms of heart failure in some patients, who may experience chest pain or discomfort, dilated neck veins irregular breathing, an irregular heartbeat, swelling of the face, fingers, feet, or lower legs weight gains.(17)

 

Over Dose:

Excessive doses of metoprolol can cause saver hypotension, bradycardia, seizures. Blood or plasma concentrations may be measured to confirm a diagnosis of poisoning in hospitalized patient(18).

 

Metabolism:

Metoprolol undergoes a- hydroxylation and O-demethylation as a substrate of the cytocrome liver enzyme CYP2D6 an a small percentage by CYP3A4 (19).

 

METHODS OF PREPARATION:

Calibration of Metoprolol: as shown in table number 2. Procedure:

1.    Weighted accurately 0.1 gm of pure metoprolol. Added water to adjust upto 100ml.

2.    Took 10ml from stock I and diluted upto 100ml with distilled water, strength of this solution is 10µg/ml.

3.    Pipette out 0.5,1,1.5 ,2,2.5.3 from stock 2.

4.    And diluted upto 10ml with distilled water

5.    Prepared blank solution without taking drug.

6.    Recorded the spectra of final solution and determined the 𝜆-max of metoprolol.

7.    λ-max was found to be222nm.

 

Table No.2: Calibration curve of Metaprolol

 

Fig No.3: Calibration curve of Metaprolol

MATERIAL:

Metoprolol succinate was obtained as gift sample from Aarti Drugs LTD, MIDC, Tarapur India. Benzoic acids, Salicylic acid, Ethanol were obtained from College Lab.

 

Preparation of Co-crystals:

·      By using Benzoic acid as co-former:

Metoprolol succinate (1gm) and benzoic acid (1gm) was dissolved in 10ml good solvent ethanol and mixture was kept for cooling in freezer. The crystal obtained were separated by filtration and dried at room temperature and stored in decicator.

 

·      By using Salicylic Acid as Co-former:

Metoprolol succinate (1gm) and Salicylic acid (1gm) was dissolved in 10 ml good solvent ethanol. And mixture was kept for cooling in frezzer. The obtained were separated by filtration and dried at room temperature and stored in desiccators.

 

Characterization of co-crystals:

1. Melting point:

Metoprolol- 150-160°C

Benzoic acid-140-142°C

Melting point of Co-crystals of metoprolol drug by using benzoic acid as a co-former was found to be in between drug and co-former-110-120°C

 Salicylic acid-158°C

Melting point of Co-crystals of metoprolol drug by using Salicylic acidas a co-former was found in between Drug and co-former-130°C-135°C

 

2. Angle of repose:

As shown in table number 3. The frictional force in powder can be measured by the angle of repose. It is the maximum angle possible between the surface of pile of powder and the horizontal plane. The blend that has angle of repose between, 20° to 30° is best for compression as it has good flow property. Angle of repose is calculated by fixed funnel method. In this method funnel was fixed to stand in such a way that the lower tip of funnel was 2.5 cm above the surface. A graph paper was placed on the flat surface. The blend was allowed to fall freely on the graph paper through the funnel, till of heap formed just touched the funnel. The radius of heap was noted and from this angle of repose was determined.

 

The angle of repose was determined using following equation,

 

=tan^-1(h/r)……………. Eq 1

 

Where,

           h=height of pile.

           r=radius of pile

Table No.3.Relation between angle of repose and flow properties

 

·      The angle of repose of metoprolol succinate was found to be Good

·      The angle of repose of  co-crystal of metoprolol succinate by using benzoic acid as co-former was found to be Excellent

·      The angle of repose of  co-crystal of metoprolol succinate by using salicylic acid as co-former was found to be Excellent

 

3. Infra-red Spectroscopy:

1. For pure Metoprolol Succinate:

Fig No.4: Infra-red of Metoprolol Succinate

 

2. Infra red spectra for Co-former Benzoic Acid:

Fig No.5: Infra red spectra for Co-former Benzoic Acid

3. Infra red spectra for co-former salicylic acid:

Fig No.6: Infra red spectra for co-former salicylic acid

 

4. Infra red spectra for Co-Crystal of Metoprolol by using Benzoic acid as conformer:

Drug+ Benzoic acid  (1:1)-

Fig No.7: Infra red spectra for Co-Crystal of Metoprolol by using Benzoic acid as conformer

 

5. Infra red spectra for Co-Crystal of Metoprolol by using salicylic acid as co-former:

Drug + Salicylic acid (1:1)-

Fig No.8: Infra red spectra for Co-Crystal of Metoprolol by using salicylic acid as co-former

Fourier Transformation-Infrared Spectroscopy (FTIR):

The possible interaction between the drug and the carrier was studied by FTIR spectroscopy. IR spectra of drug showed characteristic peaks at 2989 cm-1 (Aliphatic C–H stretch), 3271 cm-1 (Broad, intermolecular hydrogen bonded, O-H stretch), 1482 cm-1 (C–N stretch), 1378 cm-1(in plane O-H bend).

 

It was found that there were no considerable changes in the IR peaks of the co-crystals when compared to pure metoprolol succinate. In the FTIR study, the breakdown of the intermolecular hydrogen bond between the drug molecule and formation of non covalent hydrogen bond between the drug and the co-former might be related to the slight shift of the absorption band. However FTIR spectra of co-crystals showed that no changes have occurred in chemical structure. The strong interaction between drug and co-former, often leads to identifiable changes in the IR profile of the drug but the results of IR spectra indicated an absence of any well-defined interaction between metoprolol succinate and benzoic acid and / or salicylic acid (1:1).

 

Table No.4.: List of various drug on Which C-crystal has been attempted for improving physiochemical properties

Sr. No.	DRUGS	CO- FORMERS
1	Aspirin	4,4’-dipyridil
2	caffeine	Oxalic acid, Maleic acid, Malonic acid
3	Theophylline	Oxalic acid, Maleic acid, Glutaric acid , Malonic acid.
4	Sulphadimide	Salicylic Acid,   Anthranillic Acid
5	Caebamazepine	Nicotinamide,Saccharine
6	Fluoxetine hydrochloride	Benzoic acid, Succinic acid, Fumaric acid
7	Picroxicam	Saccharin
8	Norfloxacin	Isonicotinamide
9	Indomethacin	Saccharine
10	Ibuprofen	4,4’-dipyridil nicotinamide
11	Paracetamol	4,4’-dipyridil
12	flurbiprofen	4,4’-dipyridil
13	Interaconazole	Malic acid ,Tartaric acid, Succinic acid
14	Mefloquine	Benzoic acid, Oxalic acid, Citric acid, Saccharin, Salicylic acid, Succinic acid
15	Nevirapine	Benzoic acid, Oxalic acid

 

RESULT AND DISCUSSION:

The present study revealed that co-crystals of metoprolol succinate prepared with benzoic acid and salicylic acid exhibited improved the micromeritic properties. This technique might be applicable for producing oral solid dosage forms of metoprolol succinate with improved dissolution rate and oral bioavailability. Thus instead of preparation of granules, formation of co-crystal metoprolol succinate would be expected to enhance physicochemical, biopharmaceutical and tabletting properties.

CONCLUSION:

The present study revealed that co-crystals of metoprolol succinate prepared with benzoic acid and salicylic acid exhibited improved physicochemical properties. Thus, formation of co-crystals of metoprolol succinate would be expected to enhance physicochemical and micromeritics properties.

 

FUTURE PERSPECTIVES:

Work on Co-crystal can used to prove its suitability for human usage with the evolved clinical studies.

·      Co-crystal can further be processed and either filled in capsule or compressed into tablets

·      To study for its stability as co-crystals have poor stability.

 

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Accepted on 01.06.2017                             © RJPT All right reserved

Research J. Pharm. and Tech 2017; 10(11): 3761-3767.