INTRODUCTION – PHARMA GRADE ION EXCHANGE RESINS

PHAEX POLYMERS PVT. LTD. , have launched a range of Pharmaceutical grade Ion Exchange resins to cater to the various needs of Pharmaceutical industry.

These Pharmaceutical grade resins have various functionalities and polymer matrix structure and have been specifically designed to be used as Pharmaceutical excipients.

The various grades IONEX WC 20 to IONEX WC 46 have an extremely low toxicity and high Ld 50 values making them safe for human consumption. The base polymers are manufactured under the supervision of people having 15-25 years experience in this field. These various grades are used for following applications:-

  • Taste Masking of bitter drugs
  • Sustained Release
  • Vitamin B 12 Stabilization
  • Tablet Disintegration
  • Treatment of Hypercholesterolemia
  • Treatment of Hyperkalemia

Taste Masking – Theoretical Background

Use of Ion Exchange resins to taste mask the bitter drugs is an old concept. Today, it has been widely commercialized.

Many bitter drugs have amine functional groups which is the cause of their obnoxious taste. If the functional groups are blocked by complex formations, the bitterness of drugs reduces drastically. Pharmaceutical industry has been doing this kind of complex formation by converting the drugs to stearates and estolates.

This concept has been extended to block these functional group by forming a complex between Ion Exchange resin and the drug.

The advantages of using our IONEX resins are:-

  • Can be easily processed
  • Higher effectiveness as compared to traditional methods to mask the bitter taste
  • Usage in different dosage forms such as suspensions, dry syrups, dispersible tablets, tablets and capsules

Sustained Release

The rate at which a drug is released from a Drug-Resin complex is dependent on many factors. In many cases the rate is slow & the resulting effect is an extended or sustained release over many hours. Further modification can be achieved by the use of coating , that restricts the release or control the site of release. One other advantage that this technology brings is that the drug itself does not have to be in crystalline form . The resinate will be solid , with similar characteristics to the original ion exchange resin powder and , as such , can be formulated into any of the traditional solid dosage forms.

Vitamin B 12 Stabilisation

Vitamin B 12 ( Cyanocobalamine) is an unstable molecule. When used in formulations , as a normal practice 100% overages are used . Being a costly molecule, the use of such a high percentage of Vitamin B 12 increases the cost of formulation. Weak acid cation exchange resin is used to stabilise Vitamin B 12 The resin forms a stable complex with Vitamin B 12 . The overages can be reduced to 20% by use of weak acid cation exchange resin , thus drastically reducing the cost of formulation.

Drug resin ratios for complex formation

The theoretical quantity of drug, which can be complexed with resins, depends upon two factors, viz.

  • The exchange capacity of resin.
  • The equivalent weight of the drug.

The exchange capacity of the resin is mentioned in each of the product data sheet and this figure can be taken for calculating the theoretical quantity of drug which can be complexed with 1 g of resin.

Ex. The exchange capacity of IONEX WC 22 is 4.5 meq/gm. That means 1 g of IONEX WC 22 can take up 4.5 meq of the drug. Now, if the drug has an equivalent weight of 300, then 1 g of IONEX WC 22 is in a position to take up 300 x 4.5 = 1350 mg. of the drug. In a similar fashion, the theoretical quantity of the drug which can be complexed with the resin can be calculated using the equivalent weight and the exchange capacity of the resins that is being used.

The figure obtained by the above mentioned calculation is generally not valid in practice. This is due to the steric hindrance faced by the drug to penetrate the Ion Exchange resin’s polymeric structure, except for drugs having a very small molecular size. Generally for the drugs, having a molecular weight between 300-500, the required drug to resin ratio is 1:2.25, while for the drugs having a high molecular weight than 600, the required drug to resin ratio is 1:4.

Complex Preparation

Drug resinate (i.e. Complex between resin and drug) can be prepared by two methods:-

  • Batch operation.
  • Column operation.

Usually preferred mode is Batch operation due to ease of operation.

For Batch operation, the following steps are recommended:-

  • Choose a suitable solvent for the drug (preferably a polar solvent ).
  • Make 5% slurry of resin in the solvent and stir for half an hour . This will result In uniform swelling of the resin polymer structure.
  • Add required amount of drug (as per the ratio suggested above) in this slurry under stirred conditions.
  • If the drug is not soluble completely in a chosen solvent, then add the drug lot-wise over a period of 1 hour.
  • After the addition is complete, keep stirring for around 1 to 4 hours (depending on drug structure) so that most of the drug gets complexed with the resin.
  • Filter the drug resinate so formed. The filterate can be re-used to make the drug solution for the next batch.
  • Wash the resinate with distilled water. If this is to be used in suspension, it can be used as such. But if it is to be used in tablets/capsules, the resinate has to be dried at about 60°C under vacuum.

Tablet Disintegration

The effectiveness of drugs supplied as compressed tablets depends upon the ease or rate at which the tablet disintegrates in the GI tract . It is essential that the tablets possess sufficient mechanical strength to withstand the rigors of packaging , shipment and storage and at the same time disintegrate in the digestive juices and make the active constituents available for absorption during passage through the GI tract.

Varities of starch , cellulose derivatives , alginic acid and it’s salts and colloidal silicone dioxide are widely employed as tablet disintegrants in the pharmaceutical industry. Most of these materials owe their disintegrable property to the fact that they have a capacity to absorb water and swell up , causing disintegration (5) . Fine particle sized ion exchange resins have shown superiority in various tablet formulations due to their considerable swelling pressures , as they get hydrated.(6) . The advantages of ion exchange reins as compared to conventional ones are ,

  • The rate of penetration of water and the subsequent swelling is very fast and it cuts down the disintegration time substantially.
  • The ion exchange resins swell on getting hydrated but do not dissolve or have an adhesive tendency a feature commonly encountered in with gums. Thus the tablet disintegrates evenly , without forming lumps.
  • Ion exchange resins are efficient at considerable lower levels than recommended for conventional disintegrants so the formulations have low concentrations of disintegrant and the tablet size is smaller.
  • Ion exchange resins facilitate the compression phase by imparting greater hardness to the tablets.
  • Ion exchange resins work equally efficiently with hydrophilic and hydrophobic formulations,especially with the latter where the conventional disintegrants are ineffective.

Treatment Of Hypercholesterolemia

Elevated levels of cholesterol is known to be an important factor in likelihood of cardiac arrests. The biosynthesis of cholesterol is known and a key intermediate are the bile acids which are present in the GI tract . These bile acids can be bound to an anion exchange resin and so effectively removing from the body. This leads to replenishment of the bile acids through increased metabolism of serum cholesterol resulting in lowered serum cholesterol levels.

Typical dosage amounts are 8-24 g per day for extended periods.A number of different formulations are commercialised although the predominant one is a powder sachet or small container.

Treatment Of Hyperkalemia

Excess potassium in the blood is a common condition in chronic renal failure and is potentially life threatening . The action of the resin is simple ion exchange ; the resin is in the sodium or calcium form and these ions are exchanged with the excess potassium in the blood stream as the resin passes through the GI tract . Typical dosage amounts are 15-60 g per day for extended periods of time.Formulations are either powder sachets or aqueous suspensions.

Improved Dissolution of poorely soluble Drugs

The problem of dissolution of some drugs is well known . In the case of poorly soluble ionisable drugs , the release of drugs from a resinate can be faster than the rate of dissolution of the solid form of the drug. Hence one can increase the rate at which poorly soluble drugs dissolve.

The data given in the table shows the results of a USP constant volume dissolution test on an Indomethacin resinate . The footnote refers to a formulation where micronisation of the indomethacin has been used to enhance dissolution rate.

Dissolution of Indomethacin

Time , in mins.

% released ( 22 deg. C)

0

0

10

61

20

78

45

97

120

100

USP : Not less than 80% in 20 miniutes at 37 deg. C

Note that the resinate gives a dissolution rate very similar to this formulation. Note also that the test was performed at ambient temperature , not the required 37 deg. C.Increase in the temp. will increase the rate of release. Clearly , resination can be as effective as micronisation in enhancing the dissolution of poorely soluble drugs.

This rapid dissolution probably occurs because of two factors ,

Each individual drug molecule is bound to a functional site – there is no crystal lattice energy to overcome. The ion exchange matrices are relatively hydrophilic and so allow water and aqueous solutions easy access into the three-dimensional structure – eliminating problems with ‘wetting-out’ the drug.

A dramatic demonstartion of this effect was also seen during attempts to dissolve indomethacin directly into simulated gastric fluid. After three days the concentration in solution was only about 1 mg/l , compared to a published solubility of about 6 mg/l . However ,when an indomethacin resinate was put into the simulated gastric fluid , a concentration of about 6 mg/l was achieved within 30 minutes. This technique , like miconisation , increases the rate of dissolution – it does not increase the solubility of the drug.

Deliquescence

Latest discovery has been that using resinates the problem of deliquescence during manufacturing and storage can be eliminated. Resinates of deliquescent and highly hygroscopic drugs retain the properties of the resin , are not deliquescent and remain free flowing powders.

For example Sodium valproate , which is a highly deliquescent can be complexed with a IONEX SB 45 ( Cholestyramine resin) and the resulting complex ( resinate) is not deliquescent and remains free flowing powder & can be stored easily .

The implications of this discovery is that dosage forms of deliquescent or highly hygroscopic drugs could be manufactured with no special equipment or atmospheric controls , and deliquescence during storage is eliminated , simplifying the packaging requirements.

Polymorphism

Polymorphism is a very common problem in the pharmaceutical industry and huge sums of money are spent trying to identify polymorphs and trying to make stable , suitably soluble forms. A drug resinate is an amorphous solid that cannot crystallize or even form hydrates.In addition the release of the drug from the resinate is independent of the crystal form that was used to make it. Consequently using resonates completely eliminates any problems with polymorphism.

Ex. Lansoprazole resinate gives similar dissolution rates as compared to Lansoprazole in it’s original crystal form which gave different dissolution rates.

PHARMA GRADE RESINS - APPLICATION SUMMARY

1) Taste Masking

Bitter drugs are taste masked using IONEX Speciality Resins. The problem of bitter and obnoxious taste in pediatric and geriatric formulations is solved by using IONEX products in various formulations.

Following is the application list for the same ,

Sr. No.

Name of the IONEX resin

Name of the drug

1.

IONEX WC 20

Norfloxacin , Ofloxacin , Roxithromycin , Dicyclomine Hydrochloride , Nalidixic acid , Famotidine .

2.

IONEX WC 23

Chloroquin Phosphate , Chloroquin sulphate , Ciprofloxacin HCl , Quinine sulphate ,

Lebexacin HCl , Metchlopramide HCl , Amodiquine sulphate , Dioctyl sodium succinate .

3.

IONEX SC 25

Bromhexine Hydrochloride , Limoxycin HCl , Pseudoephidrine HCl , Ambroxol Hydrochloride , Salbutamol Sulphate

4.

IONEX WC 46

Nicotine* Nicotine Polacrylex , USP

2) Vitamin B12 Stabilisation

Vitamin B12 is an example of a molecule that can deteriorate on storage. This results in expensive overages. Vitamin B12 when complexed with an Ion Exchange Resin IONEX WC 20 , prevents overages.

3) Tablet Disintegrants

IONEX Speciality Resin for ex. IONEX WC 23 expand 300 on contact with moisture , thus causing effective disintegration of the tablet.

Sr. No.

Name of the IONEX resin

Name of the drug

1.

IONEX WC 23

Erythromycin Stearate , Erythromycin Estolate , Streptomycin , Levonorgestrel , Nimesulide , Amoxycillin , Sulphamethaxazole + Trimethoprim .

4. Sustained Release

IONEX Resins are formulated to a required particle size, degree of crosslinking and functionalities for specific drug release. These Resins provide uniform, prolonged and predictable drug release characteristics.

Sr. No.

Name of the IONEX resin

Name of the drug

1.

IONEX SC 28

Isoxsuprine HCl , Diltiazem HCl

2.

IONEX SC 22

Pseudoephedrine HCl , Ephedrine HCl , Phenephedrine HCl

3.

IONEX SC 25

Lincomycin HCl ,Morphine Sulfate , Codiene Phosphate , Bromhexine HCl , Dextromethorphan HBr , Neomycin sulphate

4.

IONEX SC 24

Phentermine , Amphetamine , Noscapine , Diphenhydramine , Theophylline , Lucanthone.

5) Treatment of Hyperkalemia

IONEX SC 40 ( Calcium Polystyrene Sulfonate , BP ) , IONEX SC 47 ( Calcium Polystyrene Sulfonate , JP ) and IONEX SC 25 ( Sodium Polystyrene Sulfonate , USP ) are used for the treatment of Hyperpotassium levels in Dialysis patients.

6) Treatment of Hypercholesterolemia

IONEX SB 45 ( Cholestyramine Resin , USP ) is used to reduce blood cholesterol levels .+