Suspending Agent for Extemporaneous Formulations

An oral suspension is sometimes used in situations where a normal solid oral tablet or capsule cannot be administered by the patient due to certain conditions or preferences. Also patients in the medical environment often present problems in swallowing medicines in solid dosage forms. Examples of a group of patients who have problems include patients who are very young or the elderly. Also some patients have diseases which might prevent them from being able to swallow a tablet as a whole and present with dysphagia. Some dosage forms such as chewable tablets and sprays are available to facilitate the need but they present a problem when a pharmacist needs to extemporaneously prepare the product upon a doctor’s request. Therefore a suspending agent is needed into which a tablet is crushed into or a capsule is emptied.[1]

The purpose of the suspending agent is to prevent settlement of the suspended solids under gravity. An ideal suspending agent should be easily incorporated into the formulation in a uniform manner and should easily be dissolved in water. It prevents caking by forming a loosely packed system. Ideally it should not affect the pharmacokinetics of the formulation and also should be un-reactive and non-toxic.[1,2]

The suspending agent must be able to slow the sedimentation rate of the drug, help avoid caking, provide a pseudoplastic flow and also be compatible with the active drug and also with the excipients. Such products are available commercially outside the UK and a good example of this is Ora-Plus® which will be investigated further in this study. However in the UK there are no licensed suspending agent products for extemporaneous preparation and the unlicensed products remain mostly incompatible with basic drugs.[2]

Ora-plus will be a reference point for this study as it will undergo extensive tests to find an alternative that is suited for a wide range of pharmaceutical needs. There are different forms of the product (see figure 1) available which include flavoured alternatives for children. Ora-plus is usually mixed with a drug upon a physician’s request and is then mixed with a crushed tablet or emptied capsule for ease of administration, especially in paediatric, geriatric and naso-gastric suspensions.

Ora-plus is a special suspending agent that eases extemporaneous preparation of oral suspensions forming an elegant and pharmacokinetically stable suspension. The special property that Ora-Plus® possesses is that it will remain stable and be fully functional even after being diluted up to 50% with flavouring agents, water and other solvents. This makes it ideal for the aforementioned conditions in which it is indicated for.[4]

Ora-Plus can be used in conjunction with other liquids including flavouring agents. Ora-Plus can be combined with Ora-sweet in a 1:1 ratio with 50% of each in a suspension. A full list of all the constituents of Ora-Plus if found below, these constituents work in synergy to provide good colloidal activity. The architecture behind the vehicle is a gel-like matrix which allows the particles to suspend in. The pH of Ora-Plus has been as measured as 4.5 which is slightly acidic and therefore can cause a reaction with basic drugs hence the need to formulate a drug which is more neutral.[4,5]

One of the main features of this formulation is the incorporation of four different suspending agents, which might help to explain its efficacy as an oral suspending agent wide range of situations. The first of these is Xanthan gum. This mainly consists of five sugar monomers forming a co-polymer forming a polymer. It possesses stabilisation and viscosity increasing effects. It is non-toxic and compatible with most excipients. Also it exhibits good viscosity properties over a broad range of pH and temperature. It has a viscosity of 1200-1600 mPa s (at 1% w/v solution at 25°C).There are incompatibilities that arise with other suspending agents which brings an interesting investigation to light which will be carried out in this study. This second suspending agent found in Ora-Plus® is carboxymethylcellulose which also increases viscosity and has stabilising as well as water absorptive abilities. There are different types of carboxymethylcellulose used in formulation. There is low viscosity Carboxymethylcellulose which has viscosity of 10-15 mPa s, medium is 1500-2500 mPa s and High viscosity at 8000-12000 mPa s. Carrageenan is the third type of suspending agent featured in the formulation of Ora-plus® and as with the aforementioned agents it causes stabilization as well as an increase in viscosity. Carrageenan has a range of viscosities from 5-800 mPa s at 75°C. The last suspending agent used in this formulation is Microcrystalline Cellulose. This particular agent has adsorptive capabilities and is widely used in the pharmaceutical industry. It is available as a mixture with carrageenan (Lustre Clear) and carboxymethylcellulose (Avicel).[6]

There are two main buffers or buffering agents used in this formulation the first of which is Trisodium phosphate or sodium phosphate which is often used in a variety of applications in pharmaceuticals, those include: buffering agent and also as a sequestering agent.. It is very soluble in water and insoluble in ethanol. Sodium phosphate is obtained from bone ash. The second type of buffering agent is Citric acid, which by itself cannot act as a buffering agent therefore it is combined with the sodium phosphate. It also acts under different circumstances as an acidifier or a chelating agent. However its main function remains to be adjusting pH of suspensions. It possesses an acidic taste when consumed orally. It typically has a pH of 2.2 in 1% w/v aqueous solution. Citric acid can be extracted from lemon juice as well as pineapples and purified via recrystallisation.[6]

Another ingredient or constituent that is found in Ora-Plus® suspending agent is the antifoaming agent, Dimethicone. Antifoaming agents or defoamers are used to eliminate foaming that occurs in pharmaceutical formulations, foaming can lead to several problems. These problems can include affecting temperature readins as well as density controls. Dimethicone is a silicone based antifoaming agent and they are regarded as the most efficient and most economical of antifoaming agents. Silicone based defoamers are also stable over a wide range of temperatures and are chemically inert this allows for the shaking of the suspension with minimal formation of foam.[6,7] To preserve the suspending vehicle two antimicrobial preservatives are used. The first is Methylparaben which can be used alone or in combination with other antimicrobial preservatives. Parabens are a group of preservatives to which Methylparaben belongs to are effective over a wide spectrum of pH and have a broad profile of antimicrobial activity especially against yeasts and molds. As the chain length of the agent is increased its efficacy increases, but its but water solubility decreases. Also if the agent is mixed with propylene glycol the efficacy increases. Due to the poor solubility, a salt form of the preservative is often used but this can cause problems increasing the pH of a formulation. It shows antimicrobial activity at pH 4-8, but increasing pH will in turn decrease the antimicrobial activity. The second preservative used in this formulation is Potassium Sorbate which exhibits both antibacterial and antiviral properties. Potassium sorbate is used twice as much as sorbate due to its higher water solubility. It possesses minimal protection in formulations of pH above 6. The efficacy of Potassium Sorbate is increased with temperature and increased concentration. Also the efficacy increases when used with another antimicrobial preservative such as Methylparaben, which is the main reason for the use of two preservatives in this formulation.[6]

The quantities of these constituents still remain a bit crude therefore through gel permeation chromatography a more accurate result for the quantities can be found. All these constituents provide a synergistic effect that is beneficial for Ora-Plus and the question remains as to whether all these constituents are needed to provide a good suspending agents. Therefore rheological techniques are needed to determine which constituents are redundant and which are vital for its mode of action.

The main analytical technique for finding the quantities of constituents in Ora-Plus will be Gel Permeation Chromatography (GPC). Gel permeation chromatography is the most valuable single technique in the molecular weight characterisation of polymers. The power of this technique lies in its ability to give information on the whole molecular weight distribution. To interpret this chromatogram there must be a relationship between molecular weight and elution volume. It is common practice to use narrow molecular weight standards.[8]

Aim: To formulate an oral suspending vehicle that is attuned with drugs with a wide range of pH.

Objectives:

• Provide a quantitative measure of the excipients and constituents in Ora-Plus
• Using rheological components and reverse engineering investigate whether any of the constituents are redundant and whether they can be removed or replaces
• Prepare on the basis of previous knowledge a preparation which is compatible with both basic and acidic drugs

Method:

Several tests will be done specifically gas permeation chromatography (GPC) this is to provide a good quantitative measure for the constituents in Ora-Plus. A regime of rheological testing of trial formulations using the main constituents of Ora-Plus will be conducted. This will involve testing the formulation rheologically (for example using viscometry and sedimentation rate measurement). The importance of each constituent will be assessed as each of the excipients will be removed individually which is followed by sedimentation rate and viscosity tests to see whether this has caused much of a difference. The aim is to identify and remove any insignificant components and to attempt to substitute those that are found important. The final step is to formulate new suspending agent which shall have better compatibility with basic drugs and also incorporate flavourings.

Expected outcomes: There are four different suspending agents used in the formulation of Ora-Plus and the hypothesis is that one or more will be eliminated or replaced with different agent in particular Xanthan Gum. Gel permeation chromatography will give a clearer view into the constituents and their quantities.

Limitations:

The gel permeation chromatography can only give a ratio between the constituents’ molecular weight and therefore cannot give an exact quantity of the excipients.