Introduction

Excipients play a key role in the drug product development process, facilitating the formulation of stable dosage forms while also aiding their administration. The criteria for selecting excipients, their concentration, grade, and functionality evolves along with developments in biopharmaceutical sciences, regulatory landscape as well as wider societal demands.

New drug approvals between 2007 – 2009, and 2017 – 2019

Table 1 lists the number of new drug application approvals segmented by molecule type. The data is publicly available on the FDA portal. Generic product approvals were excluded.

Table 1: New drug approvals by molecule type for the period between 2007 – 2009 and 2017 – 2019

*2019 data only up to June 2019

For the period between 2007 and 2009, the US FDA approved a total of 69 new drug applications. The majority of approvals were ‘small’ chemical entities (78.3%). Biologicals accounted for less than one fifth (i.e 17.4%). The rest of the approvals (such as contrast media agents and inorganic substances) accounted for 4.3%. Fast forward a decade on, the number of approvals is 75 but importantly, the contribution of different categories much different. Thus, while ‘small’ chemical entities still account for the bulk of approvals at 64.1%, the proportion of biologicals approved has doubled, accounting for 35% (roughly 1 in 3), pointing to the increasing importance of biotechnologically-derived medicines.

New drug approvals by dosage form

Table 2 is a breakdown of new drug application approvals by dosage form for the period between 2007 – 2009 and 2017 and 2019.

Table 2: New drug approvals by dosage form for the period between 2007 – 2009, and 2017 – 2019

Oral route still ahead, but only just

The oral route (tablets, capsules and other oral formats) accounts for just over a half of all approvals (54% during 2017 – 2019 vs 53.3% for 2007 – 2009). This is a remarkable drop from historical levels, where the oral route was the main route of drug administration, accounting for over 75% of all marketed products¹. With the increasing contribution of biotechnology to new drug discovery, the vast majority of which are delivery parenterally, it is understandable why the proportion of new drugs delivered orally has decreased.

Table 3 Frequency of dosage forms manufactured in the UK (historical data)¹

And the rest?

The data shows the inhalation, ophthalmic and topical routes are as less used today as they were a decade ago, accounting for 6.5% during the 2007 – 2009 approvals versus 5.3% for 2017 – 2019 approvals. These formats have tended to be used for very specific therapeutic objectives, and new drugs developed this way are far in between.

Excipient distribution in new drug approvals

Table 4 ranks different excipients by order of appearance in manufacturer-declared labels for those products intended to be administered orally.

Table 4: Excipients in new drug approvals (between 2007-2009, and 2017 – 2019)

Fillers and diluents

Diluents/fillers are included in solid dosage forms as a way to increase weight and improve content uniformity. Many materials have been used as diluents, including starches and its derivatives, lactose, sugar alcohols such as sorbitol, xylitol and mannitol, as well as several inorganic salts.

Data shows that a decade ago (i.e 2007-2009), microcrystalline cellulose was the most widely used filler/diluent, appearing in 51.2% of all oral products approved by the FDA. A decade on, it remains just as popular, appearing in a remarkable 68.8% of approvals. It’s multifunctional properties (filling, binding, lubricity, minimal bulk density and cost-effectiveness) put it in good stead among formulators and manufacturers, so it is no surprise how popular it is.

Lactose, which by virtue of its excellent compressibility, cost advantages and availability was one of the most commonly used filler/diluent a while back has, however, decreased in usage (from 41.5% usage to 32.8% over the period of study) while ‘newer’ materials such as mannitol are seeing a resurgence (from 24.4% to 32.8%). It is difficult to figure out the reasons for this decrease in usage but it could well be due to anxieties around lactose tolerance, perceived animal origin risks, etc.

Inorganic fillers, such as calcium hydrogen phosphate, offer different functionality to organic materials and have had their merits (density, flowability, compressibility, chemical stability, etc). Yet their usage consistently remains low among new approvals over the study period.

Tablet coatings

The data also shows that manufacturers have embraced tablet film coating technologies over the last 10 years. For example, between 2007 – 2009, 61.1% of all approved tablet were film coated tablets, which rose to 69.5% during the 2017-2019 period. A decade ago, only about 50% of new tablet approvals were film coated. Hypromellose-based coatings were the most widely used systems at 30.6% while polyvinyl alcohol-based systems accounted for only 16.7%. Today, the usage of tablet film coatings has grown to 63% as manufacturers increasingly appreciate the performance advantages of coating dosage forms. Interestingly, the popularity of polyvinyl alcohol-based systems has grown to 32.8% while that of hyromellose systems have dropped slightly to 27.9%.

Binders

Binders are some of the most essential ingredients in a formulation. Their purpose is to hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix. The data shows that povidone and copovidone are the most popular binders today, appearing in 30% of all solid dosage approvals. Usage of hypromellose has decreased over the years, dropping from 34% a decade ago to 18% today. Starch (both native and pregelatinised has also decreased from 12.2% to 6.6%. Further details are shown below:

Disintegratants and superdisintegrants

Disintegrants and superdisintegrants are used in oral solid dosage forms to cause a rapid break-up of solids as a first step to dissolution. Traditionally, the most commonly used agents included crospovidone, croscarmellose sodium, starch and sodium starch glycolate. The data shows that superdisintegrants are the most preferred materials, with croscarmellose sodium being the most popular disintegrant (appearing in just under 40% of the 2017-2019 approvals vs 31.7% during 2007-2009 approvals). The second most popular disintegrant is sodium starch glycolate (used in approx. 15% of approvals) while crospovidone is the third-most popular agent, representing 13% approvals (compared with 20% a decade earlier). Low subsitituted HPC and starch were the least used disintegrants.

Lubricants and glidants

Lubricants are materials added in small quantities to tablet and capsule formulations to improve to decrease friction at the interface between a tablet’s surface and the die wall during ejection and reduce wear on punches & dies. Lubricants also prevent sticking to punch faces and in the case of capsules, sticking to machine dosators and tamping pins. Glidants, on the other hand, enhance flowability by reducing particle-particle interactions.

Of all the lubricants available for use, magnesium stearate is by far the most widely used lubricant, appearing in 74% of new approvals in 2017-2019 (versus 61.5% in 2007-2009). It is also often the cause of a number of problems experienced in solid oral dosage manufacturing, including slowing down dissolution. As a result, newer lubricants have been introduced, such as sodium stearyl fumarate. However, its usage remains low (at 14% in 2017-2019 approvals).

When it comes to glidants, colloidal silica is the most popular glidant, being present in between 33 and 40% approvals across the years of study. Other materials, such as talc and glyceryl monostearate did appear to have fallen out of favour and are apparently absent in the studied products.

Other dosage forms

Table 5 shows a list of excipients used in the rest of product formats, i.e parenteral, topical, inhalation and oral solutions.

Table 5: Excipients used in parenteral, topical, inhalation and oral solutions dosage forms

Parenteral products

Parenteral products can be solutions, suspensions, emulsions for injection or infusion, powders for reconstitution before injection or infusion, and implants for placement into the body. When a solution is required, water for injection can be used and for less soluble actives, a co-solvent or surfactant can be utilised. In some instances, solubility enhancers such as cyclodextrins are used. A range of vegetable oils can also be used either as emulsions or to create non-aqueous solutions.

pH is one of the critical considerations when formulating parenteral products. Buffers are therefore routinely used to achieve a desired pH, which can be close to physiological pH where desired, or for the case of peptide and protein drugs, a pH that ensures stability. With the exception of Polysorbate 80, which we found routinely used in the vast majority of parenteral products (44.7% during 2017-2019 and 29.0% during 2007-2009), there was no consistency among other excipients. The buffers in use included sodium acetae – glacial acetic acid, sodium phosphate dibasic and sodium dihydrogen phosphate, tromethane, l-histidine, and glycine.

Finally, a key consideration for biological drugs, and protein molecules in particular, is the requirement for stabilization. A number of excipients are added, not only during manufacture, but also in the final formulation, to retard degradation or prevent aggregation. The six main types of materials used include buffers, salts, amino acids, polyols, disaccharides, surfactants, and antioxidants. Trehalose, sucrose and albumin were the only materials we found to be in use as stabilisers during the study period.

Inhalation, Ophthalmic and Topical Products

The final group of dosage forms to consider are inhalation (metered dose inhalers, dry powder inhalers or nebulisers), ophthalmic solutions and topical products. As the data above in table 5 shows, the number of approvals in this sub-category were comparatively few, and correspondingly, the number of excipients used.

Among the excipients of interest are preservatives – typically used in ophthalmic and topical products to limit the growth of bacteria. Within approvals, different products used different materials, including phenol, parabens, potassium sorbate, benzyl alcohol and benzalkonium chloride, with no single agent being a clear dominating material.

Concluding remarks

Excipient selection is guided by many factors, including limiting characteristics of the active ingredient, such as dose, stability, compactability, and solubility, and others such as functionality, supply availability, compatibility with the active ingredients, individual company policies as well as formulators’ familiarity with a given material.

In the 1980s and early 1990s, excipient functionality was a big deal- product developers selected excipients with quantifiable physicochemical properties. In the late 1990s and early 2000s, focus shifted to excipients that aided the optimization of API bioavailability. Later on, the rise in senior citizen population and the recognition of paediatric consumers brought to light the need for technologies that could aid ease of administration and or palatability. More recently, society’s quest for sustainability, health and wellbeing has had a noticeable uptick in the use of materials that draw upon these themes.

A period of twelve years is not long enough to allow us to draw concrete conclusions, and above all, from a limited data set that we’ve selected for analysis. Yet, there are some noteworthy changes, not least the increase in the number of biological drugs vis-à-vis ‘small’ molecules. It is not very long ago when oral dosage forms represented the bulk of approved drugs – sometimes as high as 80%. In the last decade, biotechnology has created entirely new classes of therapeutic molecules, including monoclonal antibodies, cancer vaccines, gene therapy, antisense strands, enzymes, and proteins, leading to a rapid increase in the number of parenteral drugs, which are now accounting for up to 50% of approved drugs. This will have important implications to the traditional excipient landscape, going forward.

References

1. AULTON, M. E., & TAYLOR, K. (2018). Aulton’s pharmaceutics: the design and manufacture of medicines. Edinburgh, Churchill Livingstone/Elsevier.
2. United States Food & Drug Administration. Inactive Ingredient Search for Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.
3. Hamman J, Steenekamp J. Excipients with specialized functions for effective drug delivery. Expert Opin Drug Deliv. 2012 Feb;9(2):219-30. doi: 10.1517/17425247.2012.647907. Epub 2011 Dec 23. PMID: 22196483.

Luis Carey and Danna Ritter | Pharmacentral.com Guest Writers

This study explores the use of Raman mapping to monitor blend homogeneity and low dose content uniformity of active pharmaceutical ingredients in excipient blends. Compared with wet chemistry analytical methods, this technique offers a high spatial resolution (several µm), allows the identification of specific components using marker vibrational bands and is non-destructive.

Introduction

Direct compression is by far the most preferred technique in pharmaceutical R&D and tablet production. It involves simply blending the active pharmaceutical ingredient with appropriately selected excipients which are then compressed into tablets. Thus, it eliminates many of the tedious steps that accompany wet granulation.

However, direct tablet compression can be challenging for low dose, highly lipophilic drug substances when it comes to physical stability, blend homogeneity and ultimately, content uniformity. Particular attention needs to be paid to the types of filler-diluent selected as it constitutes the bulk of the formulation.

It has also been suggested that some excipients that are fibrous in nature are ideally suited to direct compression of low dose formulations because they can help trap and ‘bind’ the active drug substance thereby preventing segregation. For more on formulation of low dose see Rohrs, Amidon and Meury et al (2006) article on formulation of low dose formulations here.

During new formulation development, it is vitally important for formulators to have access to simple but effective methods to study drug-excipient interactions beforehand as opposed to laborious wet chemistry techniques that are typically used. Furthermore, assessing the content uniformity this way requires grinding 20 or more tablets which can easily hide variations that would otherwise be visible in physical blends.

By investigating different excipients with a low dose of an API during the blending process it is possible to increase the probability of consistently producing a solid dosage form with acceptable and consistent homogeneity.

In this study, we selected three commonly used functional excipients, namely, pregelatinised starch (LYCATAB® – Roquette), Calcium Phosphate Dihydrate (EMCOMPRESS® – JRS Pharma) and Spray dried lactose (FASTFLOW® – Kerry) commonly used in the formulation of a wide range of solid dosage forms. The aim was to understand the mechanisms behind the physical interactions of the excipients with a micronized, lipophilic drug candidate using Raman FTIR spectroscopy.

Methods

Blends of indomethacin {m.w 357.79, calculated log P 4.18, D (v,4,3) 9.497)] and pregelatinized starch, spray dried lactose and calcium phosphate dihydrate were dry blended in an Apex double cone blender for 10 minutes. Samples (200 mg) were removed in triplicate from different positions within the blender using a stratified sampling technique.

Scanning electron microscope (SEM) is a type of electron microscope capable of producing high resolution images of a sample surface. Due to the manner in which the image is created they have a characteristic three-dimensional appearance and are useful for judging surface structure. SEM images were obtained for indomethacin, pregelatinized starch, spray dried lactose and calcium phosphate dihydrate and the blends thereof. The images were used to approximate particle size and investigate the nature of the interaction between the excipient and the active drug substance.

Laser sizing – Light from a laser is shone into a cloud of particles which are suspended in a transparent gas e.g. air. The particles scatter the light, smaller particles scattering the light at larger angles than bigger particles. The scattered light can be measured by a series of photodetectors placed at different angles. This is known as the diffraction pattern for the sample. The diffraction pattern can be used to measure the size of the particles using light scattering theory. Laser sizing was used to obtain the particle size of both the pregelatinised starch and indomethacin. The results were compared to those obtained by SEM to confirm particle size.

FT-Raman Spectroscopy mapping – This spectroscopic technique investigates the vibrational transitions of covalent bonds in molecules. Raman spectroscopy can be applied to a wide range of samples that includes organic and inorganic materials. FT-Raman spectra of indomethacin in the excipient blends were obtained between 0 and 4000 cm^-1 using a Thermo- Nicolet NXR FT-Raman Spectrometer, equipped with a NXR Genie detector (liquid nitrogen cooled) and a computer controlled mapping stage.

Initial data acquisition was by Smart ARK and OMNIC software. The data were subsequently analyzed using the InSight chemometrics software package. A standard configuration was used to obtain a Raman spectrum from different small areas of drug and excipient blends. Vibrational bands at 1698 cm^-1 (indomethacin), 363 cm^-1 (lactose), 478 cm^-1 (pregelatinized starch) and 988 cm^-1 (calcium phosphate) were used for analyses; from which FT-Raman spectroscopic maps of the blends were obtained.

Results & Discussion

Particle size data of the materials obtained by laser sizing are given in μm in the table below. D10 means that 10% of the particles are below the value stated, similarly for D50 and D90, 50% and 90% respectively.

Approximate sizes of the raw materials obtained by SEM are given in μm in the table below. Comments on the surface features which are expected to effect the interaction between the active pharmaceutical ingredient and the excipient are also given.

The particle size obtained from both techniques are in very good agreement. There are some larger particles of Indomethacin than were observed by SEM however a relatively small sample is analysed by SEM whereas the laser sizing is a product of several experiments each using a few grams of sample. The particle size and nature of the surface will affect both the ‘flowability’ and lubricating nature of the drug substance and excipient when they are subjected to shear in a typical the blending process.

In the case of pregelatinized starch, it is clear that the Indomethacin is attaching to the surface of that starch particles and ‘nestling’ in the crevices between the particles. The “plate-like” shape appears to be beneficial to the interaction and the distribution of Indomethacin throughout the sample appears uniform. With respect to the Lactose monohydrate, the indomethacin is held in its pores and surface detects. It appears that there is more Indomethacin observable in the case of the pregelatinised starch. As Calcium phosphate dihydrate is comparatively more crystalline, it is more difficult to observe Indomethacin on the surface and therefore difficult to compare to the other two excipients.

In each of the following Raman maps of the indomethacin excipient blends, the marker chosen is for Indomethacin; therefore red and yellow indicate the presence of Indomethacin, green and blue indicate the lack of Indomethacin. It is postulated that the yellow is indicative of Indomethacin near the surface, whereas red is at the surface. This is because there is still the characteristic intensity associated with Indomethacin present however, in the case of the yellow bands, it is not as significant as the red implying that the laser is not as focused on the Indomethacin at this point.

Only a very small selection of the maps generated in this study are presented.

Based on spatial maps of indomethacin within the different excipients which were analysed chemometrically, the results showed that pregelatinized starch exhibited good homogeneity and had the lowest agglomeration of the active ingredient. Spray dried Lactose blends showed good homogeneity but the level of agglomeration appeared to be. Calcium phosphate blends had the poorest homogeneity and the highest agglomeration. It is hypothesized that the greater level of particle-particle shear generated during blending facilitated the attainment of more homogeneous distribution of the active ingredient with pregelatinised starch.

Conclusions

SEM showed that for the Calcium phosphate dihydrate the surface was crystalline and irregular whereas the lactose monohydrate it was more porous and pregelatinized starch was amorphous containing plate like structures. These properties are expected to affect the flow ability and lubricating nature of the excipients when they are subjected to shear in the blending process.

On the basis of the results of this study, the following conclusions can be drawn:

SEM can be used to visualise the distribution of Indomethacin in different blends. Calcium phosphate dihydrate proved the most difficult to interrogate as it is so crystalline and broad in its size distribution. It was difficult to observe Indomethacin on the surface. For both Spray-dried Lactose and pregelatinized starch the Indomethacin at the surface was clearly visible either held in the pores or the plate-like surface features of each excipient respectively. The porous structure of the lactose and the plate-like irregular shape of the pregelatinised starch both appear to be beneficial to the interaction and the distribution of Indomethacin throughout the sample.

Raman mapping can be used to monitor blend homogeneity and low dose content uniformity of active pharmaceutical ingredients in excipient blends. This technique offers a high spatial resolution (several µm), enables the identification of specific components using marker vibrational bands and is non-destructive. The results of this study showed that better blend homogeneity was achieved with pregelatinized starch compared with lactose or calcium phosphate.

References

• B.R. Rohrs, G.E. Amidon, R.H. Meury, P.J. Secreast, H.M. King, C.J. Skoug, Particle Size Limits to Meet USP Content Uniformity Criteria for Tablets and Capsules, Journal of Pharmaceutical Sciences, 95 (2006) 1049-1059. https://www.sciencedirect.com/science/article/abs/pii/S0022354916320202. 10.1002/jps.20587
• M. Ficzere, L.A. Mészáros, L. Madarász, M. Novák, Z.K. Nagy, D.L. Galata, Indirect monitoring of ultralow dose API content in continuous wet granulation and tableting by machine vision, International Journal of Pharmaceutics, 607 (2021) 121008. https://www.sciencedirect.com/science/article/pii/S0378517321008140/ DOI: 10.1016/j.ijpharm.2021.121008
• V. Vanhoorne, B. Vanbillemont, J. Vercruysse, F. De Leersnyder, P. Gomes, T.D. Beer, J.P. Remon, C. Vervaet, Development of a controlled release formulation by continuous twin screw granulation: Influence of process and formulation parameters, International Journal of Pharmaceutics, 505 (2016) 61-68/ https://pubmed.ncbi.nlm.nih.gov/27041123. DOI: 10.1016/j.ijpharm.2016.03.058