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Development of a Novel Coating for Conventional Non-Functional Applications

Yasuhiro Suzuki and Tatsuya Suzuki

Faculty of Pharmaceutical Science, Toho University


Despite the wide availability of alternative formats, solid dosage forms remain the most efficient methods for delivering drug substances into the body. Tablets and capsules are comparatively easy to manufacture, being relatively fast and easy to form, and from the consumer’s perspective, the most preferred approach due to their portability and ease of administration(1).

The vast majority of approved new drug products formulated as solid dosages forms are film coated. Film coatings perform a number of functions, including the following(2):

  • achieve controlled-drug release properties
  • aid identification and reduce medication errors (EU law requires all primary dosage forms to be identifiable to prevent medication errors)
  • delay drug release, for instance, enteric release properties
  • impart aesthetic features (colour & gloss) to allow branding
  • protect sensitive active ingredients from light, moisture or heat
  • mask unpalatable or odoriferous ingredients (e.g. garlic or fish liver oil)

Film Coatings Competitive Landscape

In 2018, the global market for pharmaceutical film coatings was dominated by non-functional coatings. This category accounts for approximately 70% of the total volume output. Functional and modifying coatings account for 14.9% of the annual output, while functional, non-modifying products are responsible for the rest (i.e 13.1%)(3,4). The different percentages are represented in figure 1 below.

In 2010, IMS Health (now IQVIA) estimated that the total global immediate-release film coating excipient market was around 25,000MT p.a. Approximately 65% of this output was supplied as ready-made dry powder mixes, which currently retail at $40.0 per kilo. By comparison, the modified-release film coating excipient market is smaller (approx. 6,000MT p.a). This is based on estimates of 1.7 trillion tablets coated with immediate release coatings compared to just 100 billion for the modified release coatings. Based on these calculations, the total market for pharmaceutical coatings is easily around $1 – 1.2 billion(6).

IR Applications (25,000MT) % MR Applications (3,000MT) % Non-coating Technologies (5,000MT) %
Aesthetics 60.0 Enteric 55.0 Matrix systems 70.0
Moisture Protection 15.0 Sustained release 15.0 Hydrogels 20.0
Taste/odour masking 10.0 Controlled release 28.0 Melt extrusion 5.0
Others 15.0 Others 2.0 Others 5.0

Focussing on non-functional coatings, there are several products currently available on the market. Examples of their main attributes are shown in the table below. All these systems are simple physical mixes of a polymer, a plasticizer, a detackifier and other materials (e.g colours, flavours, etc). Their main use is simple physical coating, applied via aqueous or organic solvent spray coating in heated rotating drums.

Product Eudragit EPO Sepifilm LP Opadry II (85)
Manufacturer Evonik Seppic Colorcon
Base polymer Aminomethacylic acid Hypromellose Poly(vinyl) alcohol
Other components Only base polymer is supplied Stearic acid, Talc & MCC Lecithin, PEG & Talc
Regulatory status Pharmaceuticals, Global coverage. Not food approved Both food, nutraceuticals & pharmaceuticals approval, Global coverage Not food approved. Pharmaceutical approval – Global coverage
Ease of use Very complex, multi-step preparation requiring detailed formulation & storage One-step preparation & application process. Approx. 45min preparation One-step preparation & application process. Approx. 45min preparation
Personalization Possible Possible Possible
Coating process time Fast (1 hr for 1 MT batch) Slow (2-3 hrs for 1 MT batch) Fast (1 hr for 1 MT batch)
Cost (/kg) $30 $35 $40

A list of existing suppliers and potential collaborators for this project is shown below:


# Name Comment
1 Biogrund GmbH

Small supplier of ready-made systems based in Germany. Recent alliance with Roquette may improve market standing and penetration. Currently focussed on Northern & Eastern Europe.


Limited supplier of ready-made systems. Main experience is in the development of polymers with the most recent ones being copies of Evonik pharmaceutical coating polymers. They have an immediate release polymer – PVA-PEG co-grafted polymer. Strength is in their polymer technical expertise. They are poor at supporting the sales and marketing of their products.

3 Colorcon*

Largest supplier of ready-made film coating systems globally. Not a polymer manufacturer but alliance with Dow provides a lower cost source of polymers. Colorcon have approximately 60% global market share in Immediate Release coating systems.

4 Evonik*

Specialists in development of coating polymers. They are technically very strong but do not get involved in manufacturing ready-made coating systems. They have an alliance with Colorcon to provide polymers for a fully pigmented enteric coating systems. They are the strongest supplier for enteric and sustained release coating systems.

5 Dupont (ex FMC Biopolymer)

Do not supply any pigmented film coating systems and do not have capability or current wish to provide this service. Only coating for Immediate Release is Lustre Clear – which has proved to be unsuccessful in the market place.

6 Ashland*

Formerly known as Hercules/ISP. Manufacture their own polymers and have set up colour matching and coating laboratories around the world. They are positioning themselves to take Colorcon on as a primary supplier of ready made, pigmented coating systems. One of the few companies who have a global sales and technical network

7 Ideal Cures

An Indian supplier of ready-made coating systems trying to break-out of their home market. Most success outside of India has been in the supply of coatings for nutritionals and to small generic companies in South Asian market.

9 Sensient

ex Warner Jenkinson. They do not supply complete film coating systems and since the company focus back to the US they have lost market share and company focus.

10 Seppic

French-based supplier of ready made film coating systems. Limited sales penetration with focus mainly in Southern Europe


Objectives of this work

The main objective of this work was to develop a conventional, non-functional coating system with demonstrable enhanced ease of use and minimal impact on dissolution rate and stability of model drug substances.

Research Methodology

 The approach taken to research and develop the new coating product is described below:

Coating formulation development

The initial work involved developing prototype formulations of the coating. This entailed screening three commonly used polymers, i.e poly(vinyl alcohol) 88% doh; aminomethacylic acid copolymer (Eudragit E) and hypromellose to which the required quantities of inclusives has been added, in accordance with the established practice of pharmaceutical coatings formulation. The representative formulae are shown below:

Standard Formulae adopted for screening coating systems (amounts in %)

Poly(vinyl alcohol) Aminomethacrylate Hypromellose
Polymer 40-80 40-80 40-80
Plasticizer 1-10 1-10 1-10
Surfactant 0-2 1-10 1-5
Carbohydrate 0-10 0-10 0-10
Bulking agent 1-10 5-20
Other materials 0-5 0-5 0-5


In addition, commercially available coating products, i.e Sepifilm (hypromellose-based); Opadry (poly(vinyl alcohol) based and Eudragit EPO (aminomethacrylate copolymer – based) were prepared in accordance with their respective vendor instructions and used as comparators in this work. Methods of preparation and coating are widely reported in the literature and will not be repeated here.

A list of materials and their purposes is provided in the table below:

# Name Purpose
1 Polaxamer Surfactant/wetting agent
2 Magnesium stearate Hydrophobicity enhancer
3 Stearic acid Surfactant/plasticizer
4 Stearamide Plasticizer
5 Lecithin Surfactnat/plasticizer
6,7,8 Guar gum, Pectin & Xanthan gum Extender
9 Starch Filler
10 Polyethylene glycol (400, 1000, 3350) Plasticizer
11 Polypropylene glycol Plasticizer
12 Triethyl citrate Plasticizer
13 Glycerol monostearate Plasticizer
14 Sodium lauryl sulphate Surfactant
15 Polysorbate 80 Surfactant
16 Talc Filler
17 Titanium dioxide Colorant/Filler
18 Microcrystalline cellulose Filler/Extender
19 Trehalose Extender/Filler
20 Glycerol Plasticizer
21 Erythritol Plasticizer
22 Calcium carbonate Filler


A series of formulations was then developed using the above-listed compounds in accordance with the standard coating formulae, also listed above. Cast films were made from dispersions prepared using aqueous media of the different formulations and evaluated for various features to determine which products presented the best chances of being used as coatings. The tests ranged from tensile tests, moisture uptake/desorption, water vapour transmission rates, colour consistency and tackiness. Only films judged as acceptable/meeting set criteria were selected for further evaluation/development.

Tablet coating trials

Coating trials were undertaken in a laboratory scale Aeromatic Fielder fluid bed coater. Conditions of the test varied depending on the coating under consideration. The aim, however, was to obtain a standardized weight gain of 3-4% for each product, so the conditions were continuously adjusted to meet this criteria. Study tablet cores were made with Diltiazem hydrochloride (30%) and lactose and were compressed to achieve a fill weight of 200mg. Other materials added included magnesium stearate (0.5%); microcrystalline cellulose (15%), pregelatinized starch (15%) and aerosol (0.1%). Cores which were successfully coated were subsequently evaluated for drug release properties (in addition to the usual pharmacopoeial QC tests) which for brevity are not shown.

Dissolution (drug release) testing

Automated dissolution test were performed on diltiazem HCl tablets (30mg) due to its high solubility. All tablets coated to levels as for stability samples and test undertaken in HCl (pH 1.6); Na-acetate/ Acetic acid buffer system (pH 4.5) & phosphate buffer (pH 6.8).

Stability studies

To test for stability, three formulations of moisture sensitive drug substances (APIs) were prepared as follows: All quantities shown are %.

Aspirin Enalapril maleate Niacinamide
API 30 5.0 50
Lactose 38.9 63.9 18.9
Stearic acid 1 1 1
Microcrystalline cellulose 15 15 15
Pregelatinized starch 15 15 15
Aerosil 0.1 0.1 0.1
Fill weight 250mg 100mg 500mg


Once prepared, cores were coated with experimental and commercially-available formulations and placed on stability for periods ranging from 3months to 12 months. Conditions were standard USP stability conditions (40C/75% RH) either in a stability chamber or a desiccator containing sodium chloride slurry as the humidity provider.

Samples were removed at regular times (2 weeks, 1 months, 3 months, 6 months, 9 months and 12 months and tested for the amount of drug left after decomposition. The assay methodology was as follows:

Aspirin: RP HPLC using acetonitrile 25%/DI H2O 75% mobile phase. Acidified with 1% orthophosphoric acid (85% w/w). Elution: 1.0ml/min (Isocratic), Column temperature ambient and detection wavelength of 287nm. Both peaks for aspirin and salicylic well resolved.

Enalapril: RP HPLC using acetonitrile 25%/phosphate buffer 75% mobile phase. Buffer prepared from sodium dihydrogen phosphate (NaH2PO4) 10mM (adjusted to pH 2.2 with orthophosphoric acid 85% w/w). Elution: 1.5ml/min (Isocratic), Column temperature of 60C and detection wavelength of 215nm. All peaks well resolved.

Niacinamide: Two methods used: USP assay by simple UV at 450nm and RP HPLC (c18 column) using methanol 15%/DI H2O as mobile phase (+ 0.005M heaptanesulfonic acid and 0.5M triethylamine). Elution: 2.0ml/min (Isocratic), Column temperature of ambient and detection wavelength of 280nm. Peaks well resolved.


The results shown below are for the most promising formulation out of 4 candidates developed so far. This specific prototype was prepared using the following formula:

Purpose %
Aminomethacylate copolymer Base polymer With held
Pectin Extender/adherent With held
Stearamide or cholesterol Surfactant/plasticizer With held
Talc Filler With held
Polaxamer F127 Surfactant With held



As shown below, there are differences in dissolution profiles depending on the medium being used. It must be emphasized, though, that except those samples coated with Eudragit EPO commercial product, all samples were fast dissolving (90-100% release within 15min).

In HCl, all the five samples dissolve extremely rapidly and in accordance with the requirements for immediate release coated tablets, achieve 100% release well before the mandatory 45 minutes stipulated.

In pH 4.5 acetate buffer, again all the samples were able to achieve 100% release well-within the mandated time. These results were all as expected.

In pH 6.8 phosphate buffer, all the samples with the exception of the Eudragit EPO commercial formulation dissolved rapidly, including the novel formulation which is based on Eudragit EPO. This shows that drug release properties are enhanced with the novel product compared with the commercial formulation.

Stability studies

 Aspirin tablets (75mg)

Following accelerated stability study conditions of 40C/75% RH open dish in sealed/conditioned Sanyo MCO stability chamber (UCLan) or desiccator (validated for RH) in temperature-controlled oven (SOP) the 12-month results (aggregated) are shown below:

Key to the graph: NV – Novel formula; ED – Eudragit EPO; OP – Opadry AMB; SP – Sepifilm LP & CT – Uncoated tablets.

The results show that aspirin samples coated with the commercial formulations significantly decrease in strength over time period of study while the novel formulation is not affected as much as the uncoated samples. This shows that the novel formula does not accumulate moisture within the coating as much as the commercial products so as to cause degradation.

Enalapril Tablets (5mg)

 As in previous case, accelerated stability study conditions of 40C/75% RH open dish placed in sealed/conditioned Sanyo MCO stability chamber (UCLan) or desiccator (validated for RH) in temperature-controlled oven (SOP) for a total 365 days were used. 12-month results (aggregated) are shown below:

Key to the graph: NV – Novel formula; ED – Eudragit EPO; OP – Opadry AMB; SP – Sepifilm LP & CT – Uncoated tablets.

As in aspirin’s case, results for Enalapril also show that samples coated with the commercial formulations significantly decrease in strength over time period of study. Those coated with the novel formulation are not significantly affected and retain their viability to the same extent as the uncoated samples. This shows that the novel formula does not accumulate moisture within the coating as much as the commercial products so as to cause degradation.

Niacinamide Tablets (250mg)

The study conditions were also replicated for Niacinamide and were: 40C/75% RH open dish placed in sealed/conditioned Sanyo MCO stability chamber (UCLan) or desiccator (validated for RH) in temperature-controlled oven (SOP) for a total 365 days. 12-month results (aggregated) are also shown below:

Key to the graph: NV – Novel formula; ED – Eudragit EPO; OP – Opadry AMB; SP – Sepifilm LP & CT – Uncoated tablets.

It can be seen that this time, a mixed picture is obtained, with the uncoated and Sepifilm coated samples showing more degradation than samples coated with Opadry, Eudragit EPO and the Novel formula. On further investigation, it was found that the release of nicotinic acid exacerbated degradation of the remaining niacinamide within the tablets, hence the pictur shown does not necessarily represent the impact of the coatings.


The results show a concept that could be the basis for a unique pharmaceutical coating system. The concept is desirable for the following reasons:

1)         Innovative, scientifically validated approach for elaborating pharmaceutical polymer coatings of superior functionality with a strong scope for IP.

2)        Simplicity and wide applicability of the approach which keeps the risk of the technology not being adopted by customers low but keeping the marketability to potential purchasers high.

3)         Timing and flexibility of the technology in response to environmental and technological concerns regarding the use of solvents in pharmaceuticals.

The results demonstrate proof of principle, even though more work is required to assess scalability.


  1. R.I. Mahato, and A. S. Narang. Pharmaceutical Dosage Forms and Drug Delivery. Routledge, Boca Raton, Fl. pp: 313-335. 2012
  2. Overview of Tablet Coatings –
  3. J. E. Hogan. Film Coating Materials and their Properties. in: G. Cole, J. E. Hogan and M. Aulton. Pharmaceutical Coating Technology. Routledge, Boca Raton, Fl. pp 6-50.
  4. Tablet Film Coatings Market
  5. IMS Health (IQVIA) Internal communication

Excipient Selection Trends – A Review of US FDA Novel Drug Approvals Data

In this article, we summarise data obtained from examining label declarations about excipients used in both ‘small molecules’ and biological/protein products approved by the FDA between 2007 to 2009 and 2017 to 2019. The aim is to identify any trends in the way excipients use has changed over this time period.

Dr. Enosh Mwesigwa | Contributing Writer


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

2007 2008 2009 2017 2018 2019*
Small molecules 16 18 20 32 36 7
Biological molecules 2 4 6 14 22 5
Other 1 2 0 0 1 0
Total 19 24 26 46 59 12

*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

2007 2008 2009 2017 2018 2019
Tablets (Total)

FC Tablets

Non-FC Tablets

Matrix Tablets

Other Tablets































Hard Capsules

Soft Capsules













Other oral solutions, powders & liquids 1 1 0 2 2 0
IV, SC, IM Injections 6 17 8 18 23 6
Patches, Creams, Lotions, etc 1 2 1 0 0
Opthalmic Drops 0 1 0 2 1 0
MDIs, DPIs, Nebulisers 0 1 0 0 1 0
Others 0 0 0 0 1 0

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

Tablets 45.8
Hard & Soft capsules


Oral Solutions, Suspensions, etc 16.0
IV, SC & IM Injections 15.0
Topical (Patches, Creams, Lotions, etc) 3.0
Opthalmic solutions 1.8
MDIs, DPIs, Nebulisers 1.2
Suppositories, pessaries, etc 3.6

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)

2007 – 2009 2017 – 2019
Microcrystalline cellulose (all grades) 21 42
Magnesium stearate 24 42
Functional & Aesthetic Coatings (Total) 18 29
PVA film coatings 6 15
Hypromellose film coatings 11 13
Methacrylic co-polymers (Enteric) 1 1
Other coatings systems 0 0
Croscarmellose sodium 13 24
Colloidal Silicon dioxide 13 23
Lactose (all grades) 17 20
Mannitol 10 17
Povidone (all grades) 8 14
Hypromellose – for tablet cores 14 11
Sodium starch glycolate 6 9
Crospovidone 8 8
Sodium stearyl fumarate 2 8
Copovidone 1 4
Sorbitol 0 4
Native & modified corn starch 5 4
Carboxymethyl cellulose sodium 0 4
Flavours (all types) 1 4
Hypromellose acetate succinate 1 4
Sweeteners (Sucralose & Aspartame) 1 3
Calcium phosphate (all grades) 4 2
Hydroxypropylcellulose (all grades) 5 2
Xanthan gum, Carageenan and other gums 0 1
Sodium bicarbonate 0 1
Methacrylic co-polymers (Matrix) 0 1
Polyethylene glycol (solid grades) 1 0
Ethylcellulose 0 1
Polyethylene oxide 0 1


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 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

2007 – 2009 2017 – 2019
Polysorbate 80 9 21
Sodium chloride 7 8
Sodium phosphate (all grades) 6 8
Sodium lauryl sulphate 5 2
Polyethylene glycol 400 6 7
Cyclodextrins 1 0
Albumin 0 1
Poloxamer 188 1 1
Sucrose 4 9
Tromethane 1 2
Trehalose 0 3
Petrolatum 2 0
Tocopherol 4 0
Polydimethoxysilane 2 0
Lipid excipients (all) 1 7
Carbomers 0 10
Preservatives (all) 2 6
Potassium sorbate 0 1
Benzalkonium chloride 2 1
Benzoic acid 0 1
Phenol 0 2
Parabens 0 1
Citric acid 11
Sodium citrate 11

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.


  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.
  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.

The Use of FT-Raman Spectroscopy Maps to Predict Excipient-Drug Blend Uniformity

Luis Carey and Danna Ritter | 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.


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.


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.

Material D10 D50 D90
Indomethacin 16.10 (9.63) 40.29 (29.79) 72.12 (46.77)
Starch 1500 ® 0.64 (0.03) 1.664 (0.18) 5.407 (2.21)
Lactose 12.25 (0.55) 24.26 (6.65) 53.17 (23.88)
Calcium phosphate dihydrate 10.78 (1.36) 470.3 (232) 713.2 (99.24)

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.

Reagent Size(μm) Comments
Indomethacin 0.5–1 Glassy, Crystalline clusters, large crystals
Starch 1500 ® 10–70 Plate–like surface, irregular
Lactose 10–100 Porous, Crystalline deep surface folds
Calcium phosphate dihydrate 10–150 Crystalline clusters, irregular, aggregates

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.


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.


  • 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. 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. 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/ DOI: 10.1016/j.ijpharm.2016.03.058

Investigation of Drug Degradation in Moisture Barrier Coated Non-Hygroscopic Tablets

*Bricklane Innovations

St Johns Innovation Centre

Milton, Cambridge CB4 0WS


**Department of Pharmaceutics

UCL School of Pharmacy, University of London

29-39 Brunswick Square

London WC1N 1AX


This study investigated the moisture barrier performance of polymer film coatings on a low hygroscopic tablet formulation based on dibasic calcium phosphate dihydrate and aspirin. Tablets were prepared by direct compaction and coated with aqueous dispersions of Eudragit® L30 D-55, Eudragit® EPO, Opadry® AMB and Sepifilm® LP.

Moisture uptake was studied by dynamic vapour sorption at 0 and 75% RH (25 oC). Stability was studied at 75 %RH/25 oC for 120 days and HPLC assay used to determine aspirin content.

Uncoated tablet cores equilibrated rapidly and took up very little water (0.11±0.006 %), confirming their low hygroscopicity. The amounts for coated cores varied as follows: 0.19±0.001 (Eudragit L30 D-55), 0.35±0.005 (Opadry AMB), 0.49±0.006 (Sepifilm LP) and 0.75±0.008 (Eudragit EPO) indicating that coated cores had higher uptake.

There was a progressive decrease in the strength of aspirin in all the samples studied, with the coated cores showing more pronounced degradation of the active (mean % aspirin recovered after 4 months was 80.02±0.04 for uncoated cores compared with 78.75±0.30 for cores coated with Eudragit L30 D-55, 76.15±0.55 for Opadry AMB, 75.98±1.25 for Sepifilm LP and 66.45±1.13 for Eudragit EPO).

It is concluded that the benefits of using polymer films as moisture barrier coatings to increase drug stability in tablet formulations of low hygroscopicity are limited.

1 Introduction

Many physical and chemical properties of pharmaceutical substances are modified when they take up appreciable amounts of water (Dawoodbhai and Rhodes, 1989). During pre-manufacture processing, raw materials may come into contact with water, and some moisture may be retained as a result. Finished products can also become exposed to water vapour during manufacture, for instance while in temporary storage in the warehouse before packaging or even when in use by the patient. Water sorbed this way has the potential to alter functionality of the product, including key properties like disintegration and dissolution, and chemical and physical stability (Carstensen, 1988). For many drug products, especially those with moisture-sensitive ingredients, preventing water uptake is a key objective.

There are many ways of minimizing water uptake into dosage forms and/or preventing its interaction with active drug substances susceptible to hydrolysis. One approach involves the careful selection of excipients that are able to bind or repel water. When combined with a variety of technologies and packaging solutions, the deleterious effects of environmental water can be mitigated (Zografi and Kontny, 1986; Ahlneck and Zografi, 1990; Alvarez-Lorenzo et al, 2000).

A relatively recent innovation is the application of polymer film coatings with moisture barrier properties onto actual unit solid dosage forms (Mwesigwa et al., 2005). This approach is attractive since it provides a means of limiting moisture uptake into the product in addition to the usual benefits associated with application of polymer film coatings.

An ideal moisture barrier coating should exhibit low permeability to water vapour. Additionally, the coating should have a high moisture binding capacity so that any sorbed water can be prevented from reaching into the core.

In previous studies, the moisture uptake and permeability characteristics of polymer films commonly used as moisture barrier coatings were described (Eudragit L30 D-55, Eudragit EPO, Opadry AMB and Sepifilm LP).

These studies showed that polymer films exhibited complex moisture sorption behaviour with no discernable differentiation of permeability characteristics on the basis of hygroscopicity. Crucially for moisture barriers, there was no relationship between either sorption or permeability characteristics of cast films and functionality as protective coatings after application onto hygroscopic tablet cores. Our studies found that the levels of aspirin degradation were inexplicably higher in the coated cores than the uncoated cores despite coated samples achieving a net reduction in moisture uptake.

The purpose of the current study therefore was to investigate whether the same moisture barrier polymer films applied onto a non-hygroscopic tablet core might offer better protection and ensure the stability of a hydrolysable active drug substance.

2 Materials and Methods

2.1 Materials

Poly(methacrylic acid ethyl acrylate) copolymer (Eudragit L30 D-55, Evonik, Darmstadt, Germany), poly(butyl methacrylate (2-dimethylaminoethyl) methacrylate methyl methacrylate copolymer (Eudragit EPO, Evonik), a polyvinyl alcohol (PVA) – based coating system (Opadry AMB, Colorcon, Dartford, UK); and a hypromellose-based coating system (Sepifilm LP 014, Seppic, Paris, France) were free samples from the respective vendors.

Dibasic calcium phosphate dihydrate (Emcompress, JRS Pharma, Rosenberg, Germany) was purchased from JRS Pharma. Aspirin (USP Grade), triethyl citrate, talc, titanium dioxide, poly ethylene glycol (PEG) 6000, stearic acid, magnesium stearate, sodium lauryl sulphate, and carboxy methylcellulose sodium were all purchased from Sigma Aldrich (Dorset, UK).

2.2 Methods

2.2.1 Tablet Preparation and Coating

Tablet cores were obtained by direct compression and were based on aspirin (30%), dibasic calcium phosphate dihydrate (69.5%) and stearic acid (0.5%) using an eccentric tablet press (Manesty, Merseyside, UK). The tablet target weight was 200 mg and a breaking force strength of ≥ 70N.

Tablet core coating was undertaken in a laboratory-scale fluidized bed coater (Aeromatic-Fielder AG, Switzerland) at 40 oC. The coatings vendors’ recommended guidelines were followed to achieve theoretical dry weight gains of 1.8 % (Eudragit L30 D-55), 6.4% (Eudragit EPO), 4% (Opadry AMB), and 3 % (Sepifilm LP).

All coated and uncoated samples cores were thoroughly dried in a vacuum oven (for six hours at 40 oC) and stored in closed bottles over phosphorous pentoxide dessicant pending further tests.

The aspirin activity remaining in the tablet cores after coating application was compared with that of uncoated tablets. The degradation in coated samples was found to be less than 0.1 %.

2.2.2 Equilibrium Moisture Sorption-Desorption Studies

Moisture sorption characteristics of uncoated and coated tablet cores were studied in a dynamic vapour sorption apparatus (DVS 1, Surface Measurement Systems, London, UK).

Relative humidity (RH) was programmed to expose samples at 0% RH and then automatically switch to 75 %RH. The equilibration condition for each RH stage was set at a mass change rate of 0.001 %/min between two consecutive measurements.

All experiments were performed in triplicate at 25 oC. The results of water uptake are reported as the per cent dry basis (db) versus exposure time.

2.2.3 Aspirin Stability Studies

Stability studies were undertaken at 75% RH/25 oC in sealed glass desiccators, which were placed in a thermostatted incubator (Sanyo-Gallenkamp, Loughborough, UK). The RH condition was provided by a NaCl slurry. Sampling was undertaken periodically once a month for a total period of four months.

2.2.4 HPLC Assay

A previously validated HPLC method (Fogel et al, 1984) was used (with minor modification) with to assay the retained strength of aspirin with the tablets. The HPLC conditions were an integrated HP 1050 Series HPLC system, an Agilent Zorbax Exclipse XDB–C8 4.6×150 mm column and a water-acetonitrile system (75:25) acidified with orthophosphoric acid as the mobile phase.

3 Results and Discussion

The specific equilibrium moisture uptake data at the 0-90% RH/25C cycle for uncoated and coated tablet cores are shown in Fig. 1. We elected to use this cycle to illustrate the sorption patterns otherwise the rest of the data and analysis are based on the 0-75%/25C cycles.

The data show that uncoated cores equilibrated rapidly (within 50 min) and took up very little water (0.11 ±0.006 % dry basis). When contrasted with hygroscopic cores under the same studied (reported elsewhere Mwesigwa et al, 2008) showed that the uptake at 75% RH was 2.91 ± 0.011 % and equilibration time was 500 min. This therefore demonstrates that the sorptive properties of non-hygroscopic cores used in this study were limited, confirming the non-hygroscopicity of the excipients used in the formulation.

With respect to data for coated low-hygroscopic cores, it is clear that coated cores sorbed considerably more water than the uncoated samples and also took longer to equilibrate. There were further differences in sorption patterns of the different coatings. For example, Eudragit L30 D-55 and Sepifilm LP coated cores exhibited nearly similar uptake profiles (similar rates of mass change) but the total amounts of water sorbed were different. These differences are best illustrated in Figure 2, which shows the specific equilibrium mositure uptake at each time point.

The cores coated with Opadry AMB and Eudragit EPO exhibited slower rates of uptake. However, the Eudragit EPO coated core took longer to equilibrate and also sorbed the most amount of water (0.75 ± 0.008%). These results appear to suggest that application of the barrier coatings to non-hygroscopic cores did not slow the moisture uptake kinetics and may actually have “enhanced” uptake into the core. In effect, the moisture uptake characteristics obtained are from the applied films rather than the cores, the former being the more hygroscopic component.

This contrasts with the behaviour of hygroscopic cores previously reported, where it was observed that applied films resulted in a marked reduction in the water uptake and therefore thought to have contributed less to the sorption equilibrium of the cores.

Nevertheless, it should be noted that even with this apparent “enhancement”, the equilibrium total water uptake of coated non-hygroscopic cores was still only a fraction of that observed for the hygroscopic formulation (e.g., the equilibrium uptake at 75% RH for the hygroscopic core coated with Sepifilm LP was 2.18 ± 0.001 compared with 0.49 ± 0.060 for the non-hygroscopic core coated with the same polymer).

The distribution of water between the core and the applied film is an important performance characteristic of a barrier system. To determine the availability of sorbed moisture in the applied films and the tablet cores, it is necessary to recap the equilibrium moisture sorption and permeability data obtained with free standing cast films in our earlier report (Mwesigwa et al, 2008) together with the data in Fig. 1. The data showed that at 75% RH Eudragit EPO free film was the least hygroscopic with an equilibrium moisture uptake of 1.85 ± 0.255 %. The Eudragit L30 D-55 took up 2.59 ± 0.195 % db); followed by Opadry AMB (5.18 ± 1.169) and Sepifilm LP (9.64 ± 0.252 %).

In terms of permeability, the best barrier films were Eudragit EPO and Opadry AMB (permeability coefficients at 75% RH were 0.58 x10-6 and 0.69 x10-6 cm3 (STP) cm/cm2s.cmHg, respectively). Eudragit L30 D55 and Sepifilm LP free films with permeability coefficients of 1.58×10-6 and 1.92 x10-6, respectively. The data for the equilibrium sorption (in Fig. 1) provides an interesting contrast; for instance, it can be seen that cores coated with Eudragit L30 D-55 were the least hygroscopic, followed by Opadry AMB, Sepifilm and Eudragit EPO.

This suggests that the barrier properties of the films were not being replicated on the cores. This pattern becomes more clear when the distribution of the sorbed water between the film and the core is considered.

Table 1 displays the amounts (in mg) of moisture in the applied coatings (calculated from the product of the total uptake in % of the cast film and the weight in mg of applied coating) and the total water uptake (in mg) of the coated sample (being the product of % total water uptake and the weight in mg of coated sample divided by 100), and from which the amount of water that potentially reached the core can be easily obtained (being the difference of the two quantities). It can be seen that the Eudragit EPO coated samples had the highest amount of water in the core despite the low hygroscopicity and permeability of the free film. Eudragit L30 D-55 and Opadry AMB coated samples had the least quantities of water sorbed in the cores.

The behaviour of Opadry AMB system is of interest: the free film exhibited comparable permeability to that of Eudragit EPO but had much higher hygrocopicity, on the core, this film showed lower levels of water ingress into the core, which were comparable to Eudragit L30 D-55. Therefore, as in our previous report, there appears to be no meaningful relationship that can be established between either water sorption or permeability characteristics of free films and the protective function of the coatings on non-hygroscopic tablet cores.

When a coated tablet is exposed to moisture stress, it is expected that the applied coating will either completely repel the moisture or hold a portion of the moisture and allow the excess into the underlying core depending on its permeability and the amount that the core can accommodate at the prevailing conditions. Equilibrium sorption sorption is achieved when the water activity of the sample equals that of the surroundings.

Given that the cores have lower water attracting propensity than the coatings, the sorption equilibrium is largely directed by the more hygroscopic films. Under these conditions, the cores easily reach their maximum water holding capacity and any extra sorption above this amount is taken up by the film to the point equilibration with the surrounding RH is achieved. We propose this is the reason for the observed failure of the coatings to achieve a net reduction in the total amount of water taken up over the uncoated cores. This also accounts for the observation that total sorption of low hygroscopic cores are nearly a simple sum-total of that taken up by the core and the film.

Do the above results have any bearing on stability given the relatively low water uptake in non-hygroscopic cores? Figure 3 shows the results of the stability studies of aspirin in uncoated and coated tablet cores.

Firstly, it is apparent, just like the data for hygroscopic cores, that there was a progressive decrease in the strength of aspirin upon exposure to moisture stress in all samples. By the end of study, uncoated cores exhibited the lowest levels of aspirin degradation. It is worthy emphasising at this stage that the degradation observed in the samples was solely attributed to moisture uptake post coating in the fluidised bed coater.

As it would normally be expected that samples exhibiting the highest water uptake also show the greater aspirin hydrolysis, the outcome of the stability studies does not appear paradoxical. However, when viewed in the context of the barrier characteristics of the films or the total amount of water taken in (and in comparison to the hygroscopic cores), it can be seen that despite the non-hygroscopic cores taking up only a fraction of the amount of water taken up by the hygroscopic cores, the extent of degradation was higher in these samples. Also, as no correlation between water sorption/permeability characteristics of free standing films, total water uptake of uncoated/coated cores with the extents of hydrolysis of aspirin in the cores to which the films have been applied can be established, it would suggest that the ability to prevent drug degradation in the non-hygroscopic tablet cores is not necessarily the result of preventing moisture uptake, per se.

It is already well known that excipients play an important role in the stability of moisture sensitive actives. For instance, the influence of the particle size and pore volume distribution of dibasic calcium phosphate dihydrate on the hydrolysis of aspirin has been reported (Landin et al, 1994).

Other factors, including hardness (Lee et al., 1966); excipient type and crystallinity (Maulding and Zoglio, 1969; Ahlneck and Alderborn, 1988, Du and Hoag, 2001) have been discussed. In this present study, we found that the low-hygroscopic formulation exhibited greater degradation despite the lower levels of water uptake. In this formulation, more of the sorbed moisture was available as free water, which was more available to interact with aspirin.

It is also apparent that while coated cores sorb more water than the uncoated cores, we are inclined to believe that considerably higher levels of degradation of coated non-hygroscopic cores are a result of a combination of other factors rather than water uptake alone. We have previously proposed that when coated tablets are exposed to moisture stress, the adhesion of the coating to the core is compromised and this augments the degradation of aspirin over and above the levels that would be observed through simple permeation into the core (Mwesigwa et al, 2008).

There is already a significant body of corroborating evidence to support our proposition (Okhamafe and York, 1985, Felton and McGinity, 1997). It is widely known that adhesion is of primary importance to barrier performance and its loss compromises the ability of the coating to provide mechanical protection to the substrate (Fung and Parrot, 1980, Klages et al 1996 and Barranco et al, 2004), who have reported the formation of a water layer at a paint film-substrate boundary and associated this phenomenon with a reduction in adhesion to the substrate and greater levels of corrosion in oxidation.

4 Conclusions

This study was undertaken to understand whether the stability of a moisture sensitive active could be improved through application of moisture barrier coatings on tablet cores exhibiting low hygroscopicity. The moisture barrier coatings applied to tablet cores did not achieve a net reduction in the amount of moisture sorbed when exposed to elevated RH. The uncoated cores exhibited lower overall levels of aspirin degradation compared with coated samples. The use of current moisture barrier coatings on tablet cores with minimal water uptake characteristics does not appear to prevent the degradation of moisture sensitive actives.


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The sensory performance of masking flavours in bitter drug cocktails

By Cecile Guillon and Philippe Lepinay

Quest Pharma


The effectiveness of two commercial masking flavours to conceal bitterness of a drug cocktail made of paracetamol, caffeine, and quinine was investigated. Using a panel of 20 trained panellists it was found that masked solutions achieved a 28% reduction in bitterness perception using an Aspartame – Acesulfame potassium masking system flavoured with lemon and strawberry flavours. When the same solutions were masked with a sucralose-based masking system, the reduction in bitterness intensity was 47% for lemon flavour and 38% for strawberry flavour. This study demonstrates the effectiveness of using masking technologies in reducing bitterness intensity, however care must be taken to select a complimentary flavour for even higher effectiveness.



Among the five basic tastes, bitterness is perceived by humans as the most unpleasant, and is therefore of commercial and clinical importance for pharmaceutical products(1). Creating palatable products, in which aversive sensory attributes have been reduced, is of utmost importance.

The traditional approach to countering bitter tastes is through the use of sweeteners, flavours and other excipients carefully selected and combined in a manner which permits each ingredient to contribute complimentary attributes to the formulation. The goal is to achieve a neutral base taste, which can then be appropriately flavoured.

Sweeteners are used since being very soluble, they quickly dissolve in saliva and coat the taste buds, thwarting the interaction of bitter active substance with taste buds. However, there is a limit to the use of sweeteners. For instance, for overwhelmingly bitter actives, it is not always feasible to use large quantities of sweeteners to overwhelm such intensely bitter actives.

There is also the often overlooked issue of bitterness perception kinetics. Sweeteners such as sucrose have a fairly rapid onset of action and quickly fade away whereas most bitter chemicals linger on for a while in the mouth. Thus, even formulations containing sucrose may require the addition of specific flavour chemicals interacting with bitter receptors with a long temporal profile.

A different approach is to use compounds that compete with the bitter drug for binding with the bitter receptor on the tongue. When carefully formulated, these materials may have the effect of decreasing the perception of bitterness.

The aim of this study was to assess the effectiveness of two commercial masking flavour technologies to reduce the perception of bitterness (bitterness intensity) of drug cocktail made of paracetamol, caffeine, and quinine. To minimise grittiness and mouthfeel effects, the drug solution was suspended in a 0.05% w/w Gellan gum fluid gel.


Materials and Methods

Drug cocktail preparation

A simple cocktail of well-known bitter active pharmaceutical ingredients (quinine hydrochloride, paracetamol and caffeine) was prepared using commercially-available lemon or strawberry flavours. The drug cocktails were then masked with either an Acesulfame/Aspartame K-based masking flavour system or a sucralose-based masking flavour system in accordance with the manufacturer’s recommendations (Table 1).

Fluid gel preparation

The fluid gel was prepared following the bill of quantities shown in Table II.


The required quantities of Gellan gum was added to water and heated to 85 oC with moderate stirring. Once fully hydrated, sodium citrate was added and stirring continued. The mixture was then allowed to cool to 56 oC to form a gel. Anhydrous citric acid was added and the mixture gently sheared form a fluid gel.

The fluid gels were further characterised rheologically with the aid of a commercial theometer (Anton Paar MCR 300, Anton Paar, Graz, Austraia) using a concentric cylinder geometry. Steady state shear flow tests were used to measure viscosity and shear stress. The results are shown in Figure 2.


Sensory protocol for masking evaluation

Twenty trained panellists ranked the bitter intensity of the four solutions on a 0-10 linear scale. Each series were evaluated on separate days. Within each series, a blind balanced presentation order was used to avoid order effect. Acquisition and statistical analysis of the sensory results were performed using Fizz v.2.0 (F-Biosystemes) software.


Results and Discussion

Sensory performance of masking flavours

The traditional approach for masking bitterness uses a flavour associated with bitterness (e.g. lemon or grapefruit) in order to trick the brain to dissociate the bitterness from the taste of the base to that of the flavour. However, using red fruit flavours (e.g strawberry) which are associated with sweetness, makes consumer to link the bitterness with the base and not with the fruit flavour, which reduces the overall acceptability of the final product. This is the reason the performance of the masking flavours were assessed using two opposite flavour tonalities that exhibit opposite bitterness tolerances: lemon and strawberry.


Sucralose based masking flavors

The bitterness perceptions by 20 trained panellists of the two solutions (control, masked) are indicated in Figure 3.

Figure 3 - Bitterness intensity sucralose system

The profiles of both samples were not modified by the addition of the masking flavours. Results clearly indicate a 47% and 38% reduction in bitterness perception for the lemon and strawberry flavoured samples with a high level of statistical significance.


Aspartame/Acesulfame K based masking flavours

The bitterness perceptions by 20 trained panellists of the two solutions (reference and masked) are indicated in Figure 4.

Figure 4 - Bitterness intensity aspartame system

Results clearly indicate a 28% reduction in bitterness perception with a high level of statistical significance. The profile of the lemon was not modified by the addition of the masking flavour.

The panel described the sample as milder and sweeter than the reference. Similar benefits were observed in the strawberry flavoured product, where results indicate a 30% reduction in bitterness perception. The profile of the strawberry was only slightly modified by the addition of the masking flavour (sweeter, more caramelic).



Masking flavours can efficiently reduce bitterness intensity in very bitter drug cocktails made of paracetamol, caffeine, and quinine.



Walsh J, Cram A, Woertz K, Breitkreutz J, Winzenburg G, Turner R, Tuleu C; European Formulation Initiative. Playing hide and seek with poorly tasting paediatric medicines: do not forget the excipients. Adv Drug Deliv Rev. 2014 Jun;73:14-33. doi: 10.1016/j.addr.2014.02.012. Epub 2014 Mar 12. PMID: 24614069.



When referring to this article, please cite as: C. Guillon and P. Lepinay, The sensory performance of masking flavours in bitter drug cocktails. Pharmacentral Science and Technology Bulletin 01 (09) 2021.


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