Introduction

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⁾.

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.

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

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 %)

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:

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 %.

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.

Results

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:

Dissolution

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.

Conclusions

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.

References

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 – Pharmacental.com
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