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Preformulation for Excipients – Last Stop Before Formulation Development

Updated: Dec 12, 2021


Welcome to My Blog series in preformulation for drug development

In this fourth blog on preformulation, I will talk about excipients. Besides different roles of excipients, there is one aspect that many scientists fail to address. Most of the instability problems of a drug product come from excipients, in particular from impurities in excipients. This is not surprising, considering that most ingredients in drug product are excipients, sometimes >90% (w/w). If the order of magnitude is 10x compared to the active pharmaceutical ingredient (API), even a small percentage of (reactive) impurity in excipients, on a mol/mol basis can cause undesired reactions and thus, instability. This is more stringent for low dose formulations, where the excipient/API ratio can reach 2 orders of magnitude (100x).

To stabilize a drug product, you need excipients, and I cannot emphasize enough the role of buffers. You can do that only if you understand the components in your drug product, i.e., excipients. In the next blog series, I am going to address strategies for formulation development of biologics (stay tuned and follow clearviewpharmallc.com blogs).

Preformulation Is the Connection Between Drug Discovery and Drug Delivery

The scientific rivalry, or perhaps stubbornness at the two ends of the drug development has historic roots. It is often humbling for the drug discovery group to bring out a novel molecule with remarkable potential only to be shot down by the formulation group as a worthless exercise in taking it to a deliverable form. The preformulation group works with both ends to reduce the overall cost and the timeline of drug development. In some companies the line between preformulation and formulation is often a gray zone; those who kept the two groups separate have achieved great rewards!


Pharmaceutical Excipients Are Key to a Good Drug Product

For an API coming from drug discovery, it is important to know its solubility in organic solvents (some are also excipients) and formulation excipients; therefore, the characterization of excipients (including buffers) is a must, and many physicochemical properties can be found in the literature. Excipient compatibility is the second step and includes compatibility with the API (chemical/physical) and compatibility with other excipients. Some are functional excipients like antioxidants, complexation agents, and surfactants.

The performance of the final dosage form (bioavailability and stability) or manufacturability are dependent on the excipients, their concentration and interaction with the API and each other. No longer can excipients be regarded simply as inert or inactive ingredients: ICH Q8(R2) - Pharmaceutical Development. You need to address their physical and chemical properties, their safety, handling, and regulatory status. This is a must for novel excipients. For approved excipients, I suggest starting with the Handbook of Pharmaceutical Excipients where they are listed by functional category (as well as alphabetical order). For inhalation rout of administration, the list is much shorter; there are excipients for nebulizers, MDI, and DPI.


Solubilization by Cosolvents

Cosolvents are one of the most powerful means of solubilizing nonpolar solutes in aqueous media. They are organic compounds that are miscible with water, most are liquids but can include solids that are highly soluble in water (sugars, PEG, PVP). They have H-bond donors/acceptors that reduce H-bonding in H2O, have small hydrocarbon regions (<3) for each H-bond donor or acceptor that reduce the ability of water to “squeeze out” nonpolar solutes therefore increasing solubility. In some instance they are used for desolubilization if the solute is more polar than water (e.g., phenylalanine is desolubilized by ethanol).

Cosolvents increase the API solubility (S), but strong electrolytes (salts) reduce the solubility of nonpolar solutes. Nonpolar solutes are solubilized more efficiently than polar solutes by nonpolar cosolvents; they reduce solvent-solvent (H2O) interactions. Generally, there is a linear relationship between the log S (nonpolar) in a mixed solvent and vol.% of cosolvent. However, in some cases there is a nonlinear dependence with minima and maxima; therefore, it is important to determine the whole profile. For less nonpolar solutes there is a downward concavity of the curve at high cosolvent composition. The effect of multiple cosolvents on solubility is additive and the undesirable effects (toxicity, viscosity) are not. Do not forget that organic solvents affect the ionization constant of your API.


Buffers

Buffers are defined as systems (particularly an aqueous solution) to resist a change of pH on adding acid or alkali, or on dilution with a solvent. The water has no ability to resist change of pH. For example, CO2 from air equilibrated with water changes the pH from 7 to 5.7!

Solutions of neutral salts lack ability to resist change of pH, such solutions are called unbuffered. On the other hand, weak acids and bases resist pH changes. It is important to know the buffering capacity (the amount of strong base needed to produce a change of pH of a fixed amount, usually 1) as well as the Henderson-Hasselbalch equation behind it (see previous blogs). A perturbation of 10% acid or base (e.g., mol. fraction 0.5 to 0.6) at pH = pKa has less effect on pH than at pH = pKa ± 1. For polyprotic buffers, if the pKa values are sufficiently far apart, treat them as monoprotic (e.g., phosphoric acid). Do not forget the temperature and ionic strength dependence on pKa.

Common error alert: Never use a buffer outside its buffering capacity. Always adjust the pH of the stock so that is correct when diluted! A pH display reading of 3 decimal places gives a completely unjustified and false sense of confidence. When making buffers by the titration method, always start with the buffer species that has the lowest charge.


Excipient drug compatibility

Most of the DP stability surprises are due to excipients. One needs to know the chemical reactivity of function groups in conjunction with drug – excipient, excipient – excipient, and impurities in both (e.g., peroxides in PEG and its derivatives). The molecular mobility within the solid matrix is important, the crystal defects, localized disordered regions, and amorphous content. The adsorbed water effects the mobility and the glass transition temperature (Tg).

The old approach for excipient compatibility was a binary mixture of the drug with the excipient in the ratio of 1:1, stressing the combination followed by API analysis. However, this is not the real world. The common practice is to use low API/excipient ratio and match as much as you can the prospective formulation. Allow more physical interactions in solid state mixture (amorphous) and understand the reaction mechanisms. Physical interactions affect also physical stability.


Excipients Could Be Reactants

It is important to know your system and avoid reactive excipients. Some approved excipients are not reactive for the system they were approved for; however, they may be reactive in your formulation.

For example, when glucose (reducing sugar: can form an open chain, become aldehyde that can be oxidized; the other compound is reduced) is added to lyophilized Relaxin, the amino groups in proteins react to form glucosamine (Maillard reaction). Lyophilized Insulin with trehalose gives deamidation and dimerization via cyclic anhydride intermediate (Pharm. Res. 2006, 23, 961-966). Also, avoid deliquescent excipients; they will increase degradation. Do not forget the ink and coatings (TiO2 is light blocker but also a photocatalyst!).


Functional, Co-processed, and Novel Excipients

Functional excipients include antioxidants (vitamin E, BHT, ascorbic acid), complexation agents (cyclodextrins, EDTA), surfactants (SLS), UV-light absorber (phenyl salicylate, 2,4-dihydroxybenzophenone). For antioxidants, there are water soluble and oil soluble antioxidants (Note: for emulsions needs to be added both). Using more than one antioxidant is often effective. However, you should know their mechanism of action.

In co-processed excipients (combination of existing pharmacopeia excipients) at least one non-performance-related property must be different, produced by high-shear dispersion, granulation, spray drying (e.g., fumed silica w/ MCC), or melt extrusion.

A novel excipient is an excipient never used in a marketed product, or at a level higher than in a marketed product, or in a different route of administration. Novel excipients are treated as API for Tox, impurity profiling (including analytical methods), and physicochemical characterization. The definition of novel excipients differs from US/EU vs. JP. One should not neglect the new regulatory guidance on genotoxic (ICH M7) and elemental impurities (ICH Q3D), as well as on excipient performance (USP<1059>).

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Pharmaceutical consulting | Clearview Pharma Solutions LLC (clearviewpharmallc.com)


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