Importance Of Excipient Selection In The Process Of Oral Liquid Formulation Development

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When developing an oral liquid dosage formulation, consideration is first given to the characteristics of the active drug. The major challenges in developing oral liquid dosage forms are (i) the stability of a drug in solution, (ii) the solubility of a drug at the required level, and (iii) an acceptable taste. It is the effective use of excipients, which allows for-mulators overcome these challenges. Additionally, an excipient's compatibility with a drug in the solid state cannot infer the same compatibility in solution. However, if the mechanism of degradation of the drug is understood, the process of selecting which excipients to use in a solution will be much easier. Finally, some knowledge of the drug's physical and chemical characteristics such as the solubility, pH stability, and pKa value(s) of reactive functional groups is essential in order to choose the proper excipients effectively.

Ideally, the pH at which the drug is most stable would also be close enough to the solubility for delivering the desired dose in approximately 5 mL. Requiring patients to take more than 10 mL at a time may not be advisable because of lower patient compliance (variability). In this scenario, a simple oral solution or syrup formulation may be developed. However, if the pH at which the drug is most stable is not one at which there is enough solubility, a suspension formulation may be required.

A quick means to identify whether or not a drug may be more suitable for solution or suspension is to overlap the pH-stability profile with the pH-solubility profile. This overlap creates a window, which may suggest which dosage form might be most desirable and subsequently the type of excipients needed. The overlapped figures below demonstrate for aspirin (which is a weak acid) that the pH of greatest stability is also the pH at which there is low solubility (Fig. 1).

The decision to develop a solution versus syrup versus suspension can also be influenced by other factors. The desired release profile of the drug may lead to the

Figure 1 pH stability and solubility curves of aspirin. Source: From Ref. 3.

Figure 1 pH stability and solubility curves of aspirin. Source: From Ref. 3.

development of a suspension over a solution. In this case, excipients may be used to control or delay release of the Active Pharmaceutical Ingredient (API) from the suspension. Excipients used in an oral concentrate may also be used to protect drugs that are unstable in an acceptable pH range or that are easily hydrolyzed or oxidized by inhibiting the interaction of water with the drug. Additionally, excipients typically used in a syrup or suspension may be able to more effectively mask an extremely bitter tasting drug than a solution formulation. However, there are a variety of compounding and filling challenges for creating suspensions, which often make solutions a more attractive formulation.

Once a dosage form is chosen, this will affect the choice of acceptable excipients for screening. For a list of the excipients, which have been generally regarded as safe (GRAS) see the following Web site: http://www.cfsan.fda.gov/%7Edms/ eafus.html. In the following section, excipients, which are commonly used to develop oral liquid dosage forms, are reviewed and summarized by their functionality. The final section addresses the challenges involved in the process of formulation and product development, and various regulatory issues regarding oral liquid dosage forms.

Typically, in preformulation studies, the drug's compatibility with an excipient is studied in a 1:1 mixture, with the excipient under investigation at elevated and/ or refrigerated temperatures. When studying the compatibility of a drug and excipient for an oral solution, there are several important parameters that should be closely monitored. Changes in an excipient's viscosity, color, or pH during stability studies can drastically affect the active ingredients in solution. Polymerization or crystallization of certain excipients may also lead to changes in the API stability/ concentration/homogeneity.

Once preformulation screening has identified which excipients are able to stabilize the API, a series of prototype formulations can be developed, which will be more reflective of the targeted quantities of excipients and drugs present in the final

Solubilizers

Solubilizers

formulation. Many companies use a rapid high-throughput screening approach to determine the optimal combination of excipients for their formulation. In these mixtures, the excipient-excipient (placebo) and excipient-drug incompatibilities should be closely studied for their stability. Additionally, many of the excipients described in the following sections can be used for more than one function. The following figure gives a depiction of the overlapping functionality of some typical excipients (Fig. 2). By understanding this principle, one can develop a formulation that encompasses all the required attributes (sweetening/solubilizing/preservative), using the least number of excipients.

EXCIPIENTS USED IN ORAL LIQUID FORMULATIONS Solubilizers

In developing a formulation in which the API is dissolved in an aqueous vehicle, the first challenge is to solubilize the drug by breaking the strong hydrogen bonding of water, which causes less polar solutes to be "squeezed out.'' There are numerous approaches which may be taken to achieve the solubilization of a drug in aqueous solution. For example, the drug's intrinsic water solubility can be modified by the addition of a cosolvent, pH control, complexation, or the use of surfactants. This section focuses solely on the typical cosolvents used in oral liquids.

In aqueous-based solutions, solubilizers are used to modify the polarity of water to allow an increase in the solubility of a nonpolar drug. It is a balance between the forces of entropy that drives the solubilization of a solute and the enthalpic factors that oppose mixing of the solid (typically the API) and liquid phases (delivery vehicle) together. Some typical excipients used as solubilizers in oral liquid dosage forms are propylene glycol (PG), alcohols such as ethanol, sugars such as sorbitol, or polyethylene glycols such as PEG-400. There are many types of derivatives for each of these general groups. The ability of polymers such as polyethylene glycols or polyvinylpyrrolidones to affect solubility is dependent upon the polarity of its monomeric repeating units and end groups. However, it is not only the polarity that is altered upon addition of a solubilizer (cosolvent), but also the density, surface tension, viscosity, boiling point, and specific heat of solution, all of which may be affected in various ways.

Typically, when water-miscible cosolvents are used in combination, the effect is additive (assuming the cosolvents do not interact with each other), and the solubility of the drug is greater than in either of the individual cosolvents alone. However, the partial miscibility of two liquids (cosolvents) may occur if the free energy of a combination of two mutually saturated phases is lower than that of a single phase. Additionally, if the solute is very polar, the addition of a cosolvent may decrease the solubility of the drug. For example, the solubility of phenylalanine is decreased to a greater extent by ethanol than by PG, and least by glycerin. This is because ethanol > PG > glycerin alters (reduces) the polarity of water (3).

Complexation

Another approach to increasing the solubility of a drug in solution is to use a complexing agent such as a cyclodextrin. Currently in the United States, only hydro-xypropyl-p-cyclodextrin has been used in an oral liquid formulation. However, many other cyclodextrins are widely used outside the United States in both oral and par-enteral formulations. Although these agents are very effective, it is likely that the additional cost of this excipient and the potential approval and licensing challenges have limited the number of products that use cyclodextrins in an oral liquid formulation. Cyclodextrins have various ring sizes, which form complexes with drugs to increase their solubility and/or stability. In addition to various ring sizes, the cyclodextrins have been modified at the sugar hydroxyl groups with nonpolar and polar substituents such as dimethyl, hydroxyalkyl, or glucoside moieties. The degree of substitution can also affect the size and shape of the ring cavity and therefore the complexation of the drug.

The addition of a surfactant or cosolvent to the cyclodextrin-drug complex may have a variety of effects. The complex could be stabilized (an increase in binding coefficient) if the alcohol that surrounds the drug inside the cavity of the cyclodextrin leads to a better "fit." On the other hand, if the alcohol sterically hinders the drug from forming a complex, the solubilizing effect of the cyclodextrin will be decreased. In another scenario, when cyclodextrins are combined with a surfactant, there can be a decrease in the apparent solubility of the drug based on the surfactant being preferentially complexed with the cyclodextrin. Finally, there may be a slight change in the drug's pKa value when it is complexed. Depending on the drug, this may increase or decrease the overall stability in an oral liquid formulation. This type of change is not likely to be predicted "a priori" but may be observed if an excipient range study is performed.

Sweeteners

A sweetening agent can play a number of important roles in an oral liquid formulation such as enhancing flavor, masking bitter taste, and/or increasing viscosity. The following section describes attributes of each type of sweetener and some potential challenges in their use. To organize the different types of sweeteners used in oral liquid formulations, a distinction was made between the natural and artificial sweeteners.

Natural Sweeteners

Sucrose is the most common sweetener used in oral pharmaceutical formulations. It is produced from sugar cane and sugar beet and is recognized as nontoxic and biodegradable. Its solubility in water at 20°C is 1 part sucrose in 0.5 part water. Sucrose

Table 1 Natural Sweeteners

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Responses

  • JULIA
    Why is excipient more important in liquid dosage form?
    3 years ago
  • placido
    What are the importance of the excipients in liquid dosage forms?
    3 years ago
  • Mewael Medhane
    Why are liquid excipient forms important?
    3 years ago
  • kristi
    Why sweetening agents are important in oral formulations?
    2 years ago
  • max
    What excipient used in liquid formulation?
    2 years ago
  • Impi
    What is the purpose of drug excipient iin drug formulation?
    2 years ago
  • abbondanzio
    Does the solubility of the active ingredient affect the choice of the excipient?
    2 years ago
  • luigia
    What excipients are needed to formulate a tablet?
    6 months ago
  • maggie
    Why excipients not required in lactulose formulations?
    4 months ago
  • Marmadoc
    What are the excipients used in syrup?
    3 months ago
  • HERIBALD
    What liquid dosage forms and excipients are insyrup?
    2 months ago

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