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Formulating

European Patent Office 2020 Annual Review report published, reveals successful year, despite COVID-19 challenges

July 8, 2021

The European Patent Office published its Annual Review 2020 report on 29 June 2020. The report which was accompanied by a video, reveals a year of accelerated change as the organisation seeks to adapt to many challenges from COVID-19 pandemic.

The Annual Review 2020 shows that demand for European patents has remained nearly on a par with last year. A total of 180 250 European patent applications were received, representing a 0.7% drop compared with 2019. In addition, the Office published 133 715 European patents in 2020, -3% compared with 2019, but well above its target of 120 000.

The pandemic arrived at a time the Office was in the midst of implementing its Strategic Plan 2023. So it was necessary for the organisation to switch to a mostly virtual working model and be highly flexible. The review recognises the significance of these two factors to many of the main achievements and activities of 2020, which are outlined in the review under each of the Strategic Plan’s five clear goals.

You can find all details about this report on the EPO website or through this link.

 

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Poloxamers

June 7, 2021

What is a Poloxamer?

Poloxamers are also known as polyethylene- propylene glycol copolymer or polyoxvethylene-polyoxypropylene copolymer. They are a series of block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO).

All poloxamers are chemically similar in composition, differing only in the relative amounts of propylene and ethylene oxides added during manufacture. The presence of PEO and PPO blocks in a single polymer chain imparts to the molecule amphiphilic properties whose self-assembling properties display a wide range of phase behaviour.

Several different types of poloxamers are commercially available whose physical and surface-active properties vary over a wide range. Pharmacopoeial grades generally occur as white, waxy, granules or as solids. They are practically odourless and tasteless.

Poloxamers are listed in pharmacopoeia and generally regarded as nontoxic and non-irritant. Included in the FDA Inactive Ingredients Database (IV injections; inhalations, ophthalmic preparations; oral powders. solutions, suspensions, and syrups; topical preparations).

The general chemical structure of Poloxamers is shown below:

Generalised Chemical Structure of Poloxamer

Chemical Name Poloxamer
CAS Registration Number [9003-11-6]
Empirical Formula HO(C2H4O)a(C3H6O)b(C2H4O)aH
Molecular weight 2090 – 14 600 (average)
Regulatory Status PhEur; USP-NF; JPE
Poloxamer type Ethylene oxide units (a) Polypylene oxide units (b) Content of oxyethylene (%) Average molar mass
124 10 – 15 18 – 23 44.8 – 48.6 2090 – 2360
188 75 – 85 25 – 30 79.9 – 83.7 7680 – 9510
237 60 – 68 35 – 40 70.5 – 74.3 8740 – 8830
338 137 – 146 42 – 47 81.4 – 84.9 12700 – 17400
407 95 to 105 54 to 60 71.5 to 74.9 9840 to 14 600

Key Physicochemical Properties of Poloxamers

Acidity/aikalinity pH = 5.0—7.4 for a 2.5% w/v aqueous solution
Cloud point > 100C for a 1% w/s aqueous solution, and a 10% w/v aqueous solution of poloxamer 188
HLB value 0.5 – 30
Melting Point 16oC for poloxamer 124; 52 – 57oC for poloxamer 188; 49oC for poloxamer 237; 57oC for poloxamer 338 and 52-57 oC for poloxamer 407
Solubilitiy Solubility varies according to the poloxamer type
Surface tension 19.8 mN/m for a 0.1% w/v aqueous poloxamer 188 solution at 25C; 24.0mN/m for a 0.01% w/w aqueous poloxamer 188 solution at 25C; 26.0 mN/m for a 0.001% w/v aqueous poloxamer solution at 25 C
Viscosity (dynamic) 1000 mPas as a melt at 77C for poloxamer 188

 

How are Poloxamers Used in Formulations?

The main uses of poloxamers is as dispersing agents, emulsifying agents, solubilizing agents, tablet lubricants, wetting agents and foaming agents.

As nonionic polyoxyethylene-polyoxypropylene copolymers, poloxamers are used as emulsifying or solubilizing agents. They are used as emulsifying agents in intravenous fat emulsions and as solubilizing and stabilizing agents to maintain clarity of elixirs and syrups.

Poloxamers can also be used as wetting agents; in ointments, suppository bases, and gels; and in tablet binders and coatings. Poloxamer 188 has also been used as an emulsifying agent for fluorocarbons used as artificial blood substitutes, and in the preparation of solid-dispersion systems. More recently, poloxamers have found use in drug-delivery systems.

Therapeutically, poloxamer 188 is administered orally as a wetting agent and stool lubricant in the treatment of constipation; it is usually used in combination with a laxative such as dantron. Poloxamers may also be used therapeutically as wetting agents in eye-drop formulations, in the treatment of kidney stones, and as skin-wound cleansers.

 

Any Useful Tips?

Naming of poloxamers can be bewildering but typically, the nonproprietary name – poloxamer – is followed by a number: the first two digits of which, when multiplied by 100, correspond to the approximate average molecular weight of the polyoxypropylene portion of the copolymer and the third digit, when multiplied by 100, corresponds to the percentage by weight of the polyoxyethylene portion.

Similarly, with many of the trade names used for poloxamers e.g. Kolliphor 188, the first digit arbitrarily represents the molecular weight of the polyoxypropylene portion and the second digit represents the weight percent of the oxyethylene portion. The letters L, ‘P’, and ‘F’, stand for the physical form of the poloxamer: liquid, paste, or flakes.

Although the USP-NF contains specifications for five poloxamer grades, many more different poloxamers are commercially available that vary in their molecular weight and the proportion of oxyethylene present in the polymer.

Some poloxamers (e.g Poloxamer 188) are incompatible with parabens.

Poloxamers are used in the cosmetics field as oil-in-water emulsifiers, cleansers for mild facial products, and dispersing agents.

References

[1] R.G. Strickley, Solubilizing Excipients in Oral and Injectable Formulations, Pharmaceutical Research, 21 (2004) 201-230.

[2] G. Dumortier, J.L. Grossiord, F. Agnely, J.C. Chaumeil, A Review of Poloxamer 407 Pharmaceutical and Pharmacological Characteristics, Pharmaceutical Research, 23 (2006) 2709-2728.

[3] A.M. Bodratti, P. Alexandridis, Formulation of Poloxamers for Drug Delivery, Journal of Functional Biomaterials, 9 (2018).

 

Gellan Gum

June 7, 2021

What is Gellan Gum?

Gellan gum is a water soluble anionic hydrocolloid produced by the microorganism Sphingomonas elodea. This microorganism was discovered in 1978 in the United States by scientists at Merck following a concerted effort to find naturally occurring hydrocolloids.

Gellan gum is supplied as a free-flowing white powder. For commercial grades, gellan gum is manufactured by fermentation of a carbohydrate. In its native state, Gellan gum has acyl groups in its structure. Treatment with alkali removes acyl groups completely

Physicochemical Properties of Gellan Gum

Chemical Structure

Gellan gum is a straight chain polymer consisting of D-glucose, L-rhamnose and D-glucuronic acid units. In its native or high acyl grade, acetate and glycerate substituents are present on one of the glucose residues. The low acyl grade there is no acyl substituents. Note that the presence of acyl groups has a strong bearing on gel properties of Gellan gum.
Gellan Gum

Differences between High Acyl and Low Acyl Gellan Gum

  High Acyl Gellan Gum (KELCOGEL® LT100 Low Acyl Gellan Gum
Molecular weight 1 – 2 x106 Daltons 2 – 3 x105 Daltons
Solubility Hot water Cold or hot water
Set Temperature (oC) 70 – 80 30 – 50
Thermoreversibility Thermoreversible Heat stable

Where can you use Gellan gum?

Gellan gum is a useful and effective gelling agent in pharmaceutical and food products. It offers the following benefits:

  • It is effective at low concentrations
  • Provides a wide range of viscosities and textures
  • Gels on cooling
  • Forms fluid gels, which are solutions with a weak gel structure. These systems are extremely versatile for suspending drug substances without settling
  • Can be used in combination with other hydrocolloids

Uses of Gellan gum in pharmaceutical products

Application Typical products
Oral suspensions (immediate and sustained release) Ibuprofen, Paracetamol, Cetirizine
In-situ forming gels Nasal and ophthalmic products
Medicated gummies Vitamins and children medicines
Hair care products Stabilization of medicated shampoo formulations
Topical products Creams and lotions as a substitute for paraffins
Tablet coatings To improve slip and enhance swallowing
Oral care In toothpaste formulations to bind actives while creating a gel-like texture

Regulatory status

Approved for use in foods in Europe, USA, Japan, China and India. Gellan gum is also approved for use in non-food, cosmetics and pharmaceutical formulations in the USA, Canada, Australia, Brazil and China. Pharmaceutical use in EU falls under E418 (Directive EC/95/2). Gellan gum is manufactured in accordance with applicable food GMPs and complies with purity criteria defined in the current USP-NF monograph.

References

KELCOGEL® Gellan gum book, 5th Edition, CP Kelco, San Diego, USA

Mahdi M H et al., 2014. Evaluation of Gellan gum fluid gels as modified reléase oral liquids. International Journal of Pharmaceutics, 475; 335 – 343.

Kubo W et al., 2003. Oral sustained delivery of paracetamol from in-situ gelling Gellan and sodium alginate formulations. International Journal of Pharmaceutics, 258 (1-2); 335 – 343; 55-64

 

 

 

AEROPERL® 300 Pharma Mesoporous Silica

June 7, 2021

What is AEROPERL® 300 Pharma Mesoporous Silica?

AEROPERL® 300 Pharma is a mesoporous silica obtained by granulating colloidal silicon dioxide. Mesoporous silicas are of great interest in the pharmaceutical industry due to their unique properties, such as ordered pore structures, very high internal surface areas and availability in a variety of shapes and morphologies (spheres, rods and powders).

Scanning electron micrograph of AEROPERL® 300 Pharma

Physicochemical Properties AEROPERL® 300 Pharma Mesoporous Silica

Specific surface area (BET) m2/g 260 – 320
pH 3.5 – 5.5
Tapped density (g/l) ≈270
Average particle size (µ) 26 – 60
Pore volume (ml/g) 1.5 – 1.9
Shape Speherical

How is AEROPERL® 300 Pharma Mesoporous Silica used in Formulations?

Improving the Bioavailability of Poorly Water Soluble Drug Molecules

For poorly soluble active pharmaceutical ingredients (BCS II and IV) increasing the effective surface area in contact with the dissolution medium can enhance the rate of drug dissolution and improve bioavailability. This can be achieved by loading the drug substance in the form of small crystallites onto AEROPERL® 300 Pharma surface. Alternatively, the drug substance can be dissolved into a lipid carrier which is then adsorbed onto the mesoporous silica surface. Both these approaches result into a homogeneous and reproducible drug-loading and release.

Conversion of Liquid Lipid Formulations into Powders

Owing to its porous and highly adsorptive properties, AEROPERL® 300 Pharma can be used to change lipid formulations into powders. It is possible to use the material as a carrier and load it with up to 150% of its own weight with an oil without compromising its powder flow properties. This is undertaken via a simple blending process without the need for specialised equipment.

The high capillary forces draw the liquid into the pores. Moreover, this is a purely physical phenomenon, meaning that polarity of the lipid does not impact on adsorption – so provided the oil has reasonable viscosity, it will be adsorbed.

Inorganic Solid Dispersions via Solvent Evaporation Technique

AEROPERL® 300 Pharma has been investigated as an inorganic dispersion material for poorly soluble active pharmaceutical ingredients (API) in order to increase their dissolution rates. The API is first dispersed in a suitable solvent such as acetone, which is then added to AEROPERL® 300 Pharma. The acetone is then evaporated off resulting into adsorption of the API onto the surface of the mesoporous silica.

Enzyme Encapsulation into Mesoporous Silica for Biocatalysis

Owing to their pore size, pore structure and particle morphology mesoporous silica materials are of interest to many applications requiring enzymes to be immobilized or supported in situ. Immobilization of enzymes can result in enhanced stability, ease recovery and re-use, and allow the enzyme to be used in non-aqueous solvents where the enzyme is insoluble.

AEROPERL® 300 Pharma is ideally suited as a support material due to it mechanical and chemical stability as well as high surface area. It is also comparatively low cost and exhibits low non-specific protein adsorption properties. This means that adsorption of the enzyme is least likely to compromise the enzyme conformation or activity.

Moisture Activated Dry Granulation (MADG)

MADG is an approach to granulation carried out in a high shear granulator similar to conventional wet granulation except that the amount of water used is limited and there is no heat-based drying step. MADG starts with the addition of small quantities of water to a powder mix comprising the active ingredient(s), binder and other excipients, which is then blended under high shear to achieve agglomeration. The mesoporous silica, as the moisture absorbing excipient, is then added to the mixture to absorb excess moisture and to ‘dry’ the granules.

AEROPERL® 300 Pharma mesoporus silica offers an innovative approach to wet granulation processing. Studies have shown that AEROPERL® 300 Pharma serves as an efficient moisture absorber due to its high surface area and pore volume. The added moisture is bound effectively to create a stable, functional dry granular powder that can be readily processed via tabletting, capsule filling or dosing into sachets.

References

Ahern, R.J.; Hanrahan, J.P.; Tobin, J.M.: Ryan, K. B.; ,Crean, A.M.; European Journal of Pharmaceutical Sciences, 2013 50 400

Abdallah, N.H.; Schlumpberger, M.; Gaffney, D.A.; Hanrahan, J.P.; Tobin, J.M.; Magner, E.M.; J. Mol. Cat B: Enzymatic, 2014 108 82

Benzalkonium Chloride

June 7, 2021

What is Benzalkonium Chloride?

Benzalkonium chloride, also known as BKC, BAK or Alkyl dimethyl benzyl ammonium chloride, is a quaternary ammonium salt and a cationic surfactant with broad antimicrobial activity against bacterial, yeasts, fungi and viruses. It is a mixture of alkybenzydimethylammonium chloride, the alkly groups having lengths of 8 to 18. The general chemical structure of Benzalkonium chloride is shown below:


n = 8, 10, 12, 14, 16, 18

Chemical Name Alkyldimethyl (phenylmethyl)ammonium chloride
CAS Registry Number [8001-54-5]
Molecular Weight 354 – 360.
Regulatory Status PhEur; USP-NF

Physicochemical Properties of Benzalkonium Chloride

Physical form

White or yellowish-white powder, gel or gelatinous flakes
Acidity/alkalinity pH 5-8 (10% w/v aqueous solution)
Melting point 40 oC
Partition coefficients The octanol; water partition coefficient varies with the alkyl chain length of the homolog: 9.98 for C12, 32.9 for C14 and 82.5 for C16.
Solubility Very soluble in water and ethanol. Aqueous solutions foam when shaken, have a low surface tension and possess detergent and emulsifying properties.

How is Benzalkonium Chloride Used in Formulations?

Benzalkonium chloride is widely used in inhalations, IM injections, nasal, ophthalmic, and topical preparations as an antimicrobial preservative, antiseptic, disinfectant, solubilizing and wetting agent. It is used in similarly to other cationic surfactants, such as cetrimide.

In ophthalmic preparations, benzalkonium chloride is the preservative of choice and one of the most widely used preservatives, at concentrations of 0.01-0.02% w/v.

Antimicrobial activity can be enhanced, particularly against strains of Pseudomonas, benzalkonium chloride, through combination with other preservatives or excipients, such as 0.1% w/v Disodium edetate, phenylethanol or chlorhexidine.

In nasal formulations, benzalkonium chloride is used at a concentration of 0.002-0.02% w/v. Levels of 0.01% w/v have also been utilized in small-volume parenteral products.

Benzalkonium chloride can also be added to topical medical devices, antiseptic wipes and cosmetics as an alternative to parabens. It produces significantly less stinging or burning compared with isopropyl alcohol and hydrogen peroxide when used in topical products.

 

Any Comments and Useful Tips?

Benzalkonium chloride solutions are active against a wide range of bacteria, yeasts, and fungi. Activity is more marked against Gram-positive than Gram- negative bacteria but minimal against bacterial endospores and acid-fast bacteria. The antimicrobial activity of Benzalkonium Chloride is greatly dependent on the alkyl composition of the mixture.

Note that benzalkonium chloride has been associated with ototoxicity when applied to the ear. Prolonged contact with the skin may cause irritation and hypersensitivity. Benzalkonium Chloride is also known to cause bronchoconstriction in some asthmatics when used in nebulizer solutions.

Benzalkonium chloride is not suitable for use as a preservative in solutions used for storing and washing hydrophilic soft contact lenses, as the Benzalkonium Chloride can bind to the lenses and may later produce ocular toxicity when the lenses are worn.

Local irritation of the throat, oesophagus, stomach, and intestine can occur following contact with strong solutions (>0.1% w/v).

 

References

[1] F.G. Casablancas, Novo Nordisk Pharmatech A/S.

[2] H.S. Bean, Preservatives for pharmaceuticals, J. Soc. Cosmet. Chem, 23 (1972) 703-720.

[3] B.B. Tarbox., et al., Benzalkonium chloride. A potential disinfecting irrigation solution for orthopaedic wounds, Clinical orthopaedics and related research, (1998) 255-261.

[4] C. Boukarim, S. Abou Jaoude, R. Bahnam, R. Barada, S. Kyriacos, Preservatives in liquid pharmaceutical preparations, J Appl Res, 9 (2009) 14-17.

“Natural”, “Naturally-Derived” and “Nature Identical” Excipients and Ingredients

May 26, 2021

A product’s label is a window in its soul, that’s what the product stands for, its benefits to its consumers. Claims such as ‘Natural’, ‘Fresh’ or ‘Artificial’ have a particular resonance with consumers, playing a key role in shaping purchase decisions and other behaviours.

Within the personal care and food/nutrition sectors, ‘natural’ status carries a lot of acclaim, as evidenced from the ever increasing sales of natural products or those with ‘natural’ claims. Natural skincare and nutrition brands have been growing at twice the rate of conventional products, a trend product developers and marketers seem to know very well about.

In the pharmaceutical sector, natural claims, while not carrying similar implications, are still important. Not only are there many excipients and active ingredients, including carbohydrate polymers, gums, surfactants, oils, flavours, alkaloids and antibiotics that are natural in origins or are naturally derived but consumers everywhere are increasingly seeking natural products due to their perception as being sustainable and friendly to the planet.

However, despite the widespread use of the term natural, the definitions of the terminology around natural, natural origin or artificial remains, to this day, in the regulatory equivalent of ‘no man’s land’. Regulators are as yet to provide official definitions or guidance on what is natural or not. Maybe because of the legal ambiguity, consumer groups and lawyers have been pushing for restrictions and/or legal redress on the uses of ‘natural’ and claims around ‘no artificial’ ingredients.

Consider xanthan gum, a gum that is widely used in the food, personal care and pharmaceutical products. Xanthan gum is produced by the bacterium, Xanthomonas campestris, which converts glucose into the gum. The process is a ‘natural’ fermentation process that occurs at its own pace without human intervention. Yet controversy as to whether xanthan gum is a natural product or not persists. Manufacturers using xanthan gum and attaching ‘natural’ claims to it have been a target of lawsuits challenging the ‘natural’ status of this material.

So what do ‘natural’ and ‘naturally derived’ mean?

This is by no means a definitive, legal guide. The FDA has not provided a regulatory definition of what natural entails when it comes to regulated products. The EU has guidelines on the use of ‘natural’ for nutritional claims (Regulation (EC) 1925/2006 but when it comes to other product groups, there still remains ambiguity. Therefore the use of the term ‘natural’ in advertising or labelling requires good judgment and legal counsel to avoid legal jeopardy.

Nevertheless, a material is considered ‘natural’ when it is ordinarily identified in nature, obtained and used in its natural, raw state after being extracted from the source. For example, Virgin Almond Oil Ph. Eur is the oil obtained by cold expression of the ripe seeds of Prunus dulcis. No further treatment (refining) or additives have been added.

The types of ‘permitted’ treatments include physical, enzymatic or microbiological processes on the plant or animal source material.

A material is referred to as ‘naturally derived’ or ‘natural origin’ when the natural source is treated to access other properties of the natural raw material; for example, getting natural fatty acids and natural fatty alcohols from a coconut.

By way of an example, natural fatty acids may require further processing in order to unlock or create certain aspects of the material’s properties beneficial for its function. Equally, potassium benzoate and lecithin require extraction and purification before they are in a state suitable for performance as preservatives or emulsifiers. Provided they are from plants, these materials can be classified as naturally derived.

A less encountered term is ‘nature identical’ which is typically used in relation to flavours. Nature identical flavours (vs artificial flavours) are flavours obtained by synthesis or isolated through chemical processes. The components are chemically and organoleptically identical to flavouring components present naturally present in nature. From a regulatory perspective, nature identical and artificial flavours are undistinguishable.

Standards and Certifications

A number of international standards and certification schemes on naturalness have been developed in recent times. They aim to help raw material suppliers and product manufacturers harmonise definitions on ingredient definitions and guide consumers. Although initially aimed at the cosmetics sector, the technical definitions and qualification schemes are equally applicable to food and pharmaceutical ingredients.

Below are three of the most important standards and schemes:

The COSMOS-standard

The COSMOS-standard was introduced in 2010. It aims to define and implement a standard for organic and natural cosmetics. The COSMOS standard includes guidelines on origin and approved processing procedures of the ingredients if they are to qualify as natural or organic. In addition to ingredients, the COSMOS standard also defines naturalness of the total product.

NaTrue Standard

The NaTrue Standard was developed by the NaTrue Scientific Committee Criteria and Label, an international non-profit organization. Its main focus is on cosmetics for which it seeks to clarify and promote natural and organic cosmetics globally. For ingredients, the NaTrue Standard differentiates between natural substances, nature-identical substances and derived natural substances, with a list of approved treatment processes. Furthermore, there are positive lists available for nature-identical substances, comprising pigments, minerals and preservatives.

 

ISO 16128

The ISO 16128 is a standard from the Geneva-based International Standard Organization. It aims to provide “Guidelines on technical definitions and criteria for natural and organic cosmetic ingredients and products”. ISO 16128 consists of two parts. Part 1 provides definitions for different ingredient categories. Part 2 describes the procedure on how to calculate the naturality of ingredients and the natural origin content of a cosmetic formulation, based on the amount of natural components in each raw material.

 

Conclusions

Even with the availability of standards and certifications the distinction between natural and unnatural is not always clear. In the absence of regulatory guidance, it falls to the formulator and marketer to make their own decision about what is natural and what is not, as there is no absolute definition, only opinions. This technical note will hopefully assist you in navigating the maze of natural and artificial ingredients.

Formulating

A Fail-Safe Guide to Taste Masking Oral Products with Ion Exchange Resins

May 25, 2021

What are Ion Exchange Resins?

Ion Exchange Resins (IER) are synthetic pharmacopoeia grade water insoluble cross-linked polymers that contain a salt-forming group at regular positions on the polymer chain and have the capacity to exchange counter-ions in aqueous solution.

IERs were developed in the 1930s for water purifications applications. In the 1950s, they were introduced in the pharmaceutical industry as APIs and excipients. Currently, IERs are varyingly utilised as pharmaceutical excipients for controlling drug release agents (matrix tablets), solubility enhancement, increasing stability, taste masking and abuse deterrents.

Although there are many grades of IERs, only two materials currently meet official compendial requirements and are widely recommended for use in products. These are Polacrilin Potassium NF and Sodium Polystyrene Sulfonate USP-NF.

 

Selection and Grades of IERs

Polacrilin Potassium NF Sodium Polystyrene Sulfonate USP
Chemical Description Potassium salt of a cross-linked copolymer of methacrylic acid and divinylbenzene Sodium salt of a sulfonated copolymer of styrene and divinylbenzene
Physical Form White, fine or granular powder White, fine powder
Pharmacopoeia USP-NF USP-NF
Solubility Insoluble Insoluble
Hygroscopicity Hygroscopic Hygroscopic
Type Weak acid Strong acid
Functional Group -COO- -SO3–
Exchangeable Cation Potassium Sodium
pH Dependence Yes No
Commercial Grades AMBERLITE™ IRP88 (Dow)

KYRON T-134 (Corel Pharma)

 AMBERLITE™ IRP69 (Dow)

KYRON T-154 (Corel Pharma)

 

Advantages of IERs

  • IERs are highly versatile – they can be used in most oral drug delivery systems, including ODTs, tablets, chewable and effervescent tablet, capsules as well as dry syrups and liquid suspensions.
  • IERs can significantly improve safety and patient adherence by helping mask bitter tastes, improve bioavailability and reduce pill burden
  • IERs have a long history of use – spanning over 50 years of safety data.
  • IERs are simple to use – they do not require major changes to equipment or processes.

 

How to use IERs for Taste Masking

IERs provide an effective means to bind the bitter active principle onto an insoluble matrix via a simple ion exchange reaction. The reaction is a reversible, selective and stoichiometric exchange of ionic species that have similar charges.

The wet taste-masked complex can be used for suspension formulation directly. Alternatively, it can be dried and used in tablet, capsule or dry syrups.

The process of using IER for taste masking could not be any easier. There are two main ways to load the drug (API) on to the EIR: column method and batch method. The column method involves passing a highly concentrated solution of the API through a column of resin particles until equilibrium complexation is achieved. The batch process involves agitating a solution of the drug with a quantity of the IER until equilibrium complexation is achieved.

Generally, the batch method is preferred as it is simple and straightforward. A predetermined amount of drug is loaded onto the IER, the quantity added mainly influenced by the cation exchange capacity (which is a measure of an IER’s ability to hold exchangeable cations and therefore bind the API). The other factors that influence loading are the IER’s selectivity for the API, particle size, porosity and degree of crosslinks.

To start, it is important to identify the most ideal IER for the API. If not sure, consult your supplier for guidance. However, a simple screening process can be done that involves preparation of 1% w/v API solution to which the IER is added in different ratios, e.g 1:1, 1:2, 1:3, etc. The blends are stirred for up to 20 hours and sample solutions taken at regular interval in order to assay for free, uncomplexed drug. The most suitable IER is then one with the lowest amount of free drug (concentration remaining in solution).

The process is illustrated below:

Once the equilibration is completed, the IER-API complex can be washed, and used as is in syrups and suspensions or dried and blended with other excipients and compressed into tablets of choice or filled into capsules.

 

Usability Rating

References

Martel, J. J et al., 1981. Acid type ion Exchange resins and their use as medicines and compositions containing them. Patent EP27768.

Felton, L. A., 2018. Use of polymers for taste-masking pediatric drug products. Drug Devt Ind. Pharm 44, 1049 – 1055.

 

A day in the life of a Biotech start-up founder

May 23, 2021

As part of a new series, we’ll interviewing different people in the biopharmaceutical R&D space – including scientists, founders and noteworthy leaders – to show what day-to-day life looks like for them.

To kick this off, we recently interviewed Dr.Alvaro Goyanes (pictured), Co-founder and Development Director of London-based FabRx Ltd., a specialist biotech company at the forefront of 3D printing technologies and personalised medicines.

Please tell our readers about yourself

I am Dr Alvaro Goyanes and my current role at FabRx is Development Director and Lead Project Researcher. I am a pharmacist by training, I hold a PhD in pharmaceutical technology from University of Santiago de Compostela (Spain) and I have been at University College London (UCL) – School of Pharmacy as a researcher and as a honorary lecturer for more than 8 years. I have over 10 years’ industry experience in research and academia.

How did the idea for FabRx come about?

I can’t say there was a specific light bulb moment. During my post-doctoral studies here at UCL School of Pharmacy, I was involved in the investigating the potential use of 3D printing to make medicines. It was then that we zeroed on using Fused Deposition Modeling (FDM) that we saw a potential business opportunity, and the idea grew from there.

Having set up FabRx Ltd, what does a typical day look like for you?

Firstly, there is no such thing as a typical day. However, there are things that I do most days. Typically, I start once I am done with my morning routine (exercise, shower, coffee and time to read newspapers), I head off into my home office to get a head start on my emails before any other work starts. Typically, I may have 180 – 200 emails.

I may have business calls with the leadership team or investors, which I attend to first thing. Otherwise, my most important task is providing customer support for FabRx’s M3DIMAKER™ and the necessary communications side of things. Being responsible for development, I will be working to understand how they use our products and obtaining their suggestions as to how to improve. I may also pop into the laboratory to investigate something in relation to the development programme but this is dependent on other things going on.

Obviously, being a start-up company, a good part of my work is supporting the rest of the team with respect to the company’s long-term goals. A large part of this will be meeting all sorts of stakeholders, potential investors, customers, to build relationships and communicate our mission and what we are seeking to achieve.

And finally, I have internal meetings to support our team members in their roles and to feedback on proposed improvements to our products and research programmes, which is very critical to a start-up company such as ours.

Can you tell us more about M3DIMAKER™?

M3DIMAKER is the world’s first pharmaceutical printer in the market that we developed at FabRx. It is designed to prepare personalised medicines close to the patients, and it is mainly oriented to be placed in pharmacies and hospital, to prepare the medicines under GMP conditions. Since it was designed by us, it is specially adapted to print medicines safe and easy.

https://www.youtube.com/watch?v=404atdYX-nk&ab_channel=FabRx

What is the most challenging aspect of your job?

As you well know, for any initiative to succeed, company leaders must have a set of clear priorities to make it happen. I think the most challenging thing for me is prioritising every day and getting all issues aligned to the startup’s long-term mission. I find that there are always a million things I could be working on, be it R&D, communications, selling, motivating the research team, setting strategy, the press…. So figuring out what is worth my time and taking that decision not knowing the end outcome is not easy. As a start-up in a niche space, we do not have a playbook, which is great but also leads to a lot of decision fatigue in this respect.

And what about the most rewarding?

Without a doubt, the most rewarding part of the role is seeing the company grow and create an impact in patient’s lives. We really believe in personalised medicine and think that 3D printing is the best technology to reach it. But make no mistake, founding something is hard work, and there are some dark moments, but what lifts my spirit is when we get feedback from the doctors and users. This is worth all the hard work.

Were you always cut out to be an entrepreneur?

I do not pay attention to labels, such as entrepreneur this or that. What has always motivated me is to make a positive impact to my community and those I interact with daily.

What advice would you have for future and current founders?

Be prepared to wear a lot of different hats and face challenges.

You can find out more about FabRx and its products from www.FabRx.co.uk

 

Carbomers: Overview, Key Properties and Formulating Tips

May 20, 2021

Carbomers are an important group of excipients that every well-meaning formulator should become familiar with. Here is a quick run-through of what they are, uses and formulation tips.

Carbomers: Overview, key properties and formulating tips

Chemistry and Physical Description

Carbomers are synthetic, chemically related, high molecular weight, nonlinear polymers based on crosslinked acrylic acid chemistry.

Originally developed by BF Goodrich and trademarked CARBOPOL® in 1958. These materials (especially, Carbopol 940, 941, and 934) revolutionised topical products by enabling formulators to create new types of product previously not possible.

The general chemical structure of carbomers is shown below:

Key Physicochemical Properties

  • Molecular weight 700 kDa to 4 000 000 kDa
  • Hygroscopic
  • Powdered carbomers have a dry particle agglomerated size of 2-7µm.
  • Do not dissolve but swell in ethanol, water, propylene glycol and glycerin to form microgels.
  • Dispersions are acidic with a pH ~3. Upon neutralization (pH 7), particles swell to around 1000 times their initial volume and the viscosity dramatically increases due to charge repulsion.
  • Can produce clear gels in water and ethanol due to refractive index matching.
  • Highly crosslinked carbomers are commonly used as super absorbers in disposable diapers.
  • Salts can decrease viscosity by reducing the charge repulsion.

Applications

  • Carbomers are listed in the USP-NF, PhEur, BP; JP, IP and ChP.
  • Grades with residual benzene content > 2 ppm do not meet the specifications of current pharmacopoeia monographs.
  • Carbomers with low residuals of other solvents other than the ICH-defined Class 1 – 2 solvents may he used in Europe.
  • Carbomers with low residuals of ethyl acetate, such as Carbopol 971P NF, are permitted for use in oral preparations, e.g suspensions, capsules or tablets.
  • For topical products, carbomers can be used as gelling agents (0.1 – 2.0%), controlled-release agents (5 – 30.0%), emulsifying agents (0.5 – 1.0%), emulsion stabilizers (1.0%), rheology modifiers (0.5 – 1.0%) and stabilizing and suspending gents (0.5 – 1.0%).
  • Carbomers are also employed as emulsifying agents in the preparation of oil-in-water emulsions for external administration.
  • Carbomers can be used as bioadhesive polymers (0.1 – 0.5%), tablet binders (0.75 – 3.0%) and controlled release agents.
  • Carbomers can aTopical medical devices (Ultrasound adhesive gel and personal and medical lubricants, and artificial tears)

Advantages

  • Versatile and multifunctional excipients for oral (solid and liquids) and topical formulations.
  • Synthetically derived, hence free from irregularities of natural products.
  • Available in multiple grades and properties to meet different formulation or product performance requirements.
  • Highly efficient thickeners at very low levels (<1% polymer). Suspensions and emulsions are efficiently stabilised due to the high yield value gels.
  • Can make aqueous or alcoholic clear gels.
  • Can make emulsifier free oil in water crème gel formulations.
  • Can make stable water in oil in water emulsions.
  • Excellent skin feel (<.5%) and shear thinning rheology.

Formulating Tips

Picture credits: Silverson FLASHBLEND Mixer

  • Lightly cross-linked carbomers (lower viscosity) are more efficient at controlling drug release compared with highly cross-linked carbomers (higher viscosity).
  • If used in wet granulation processes, water, solvents or their mixtures can be used as the granulating fluid. To control tackiness of the wet mass include talc in the formulation.
  • Carbomers from different manufacturers or grades produced via different manufacturing processes may not have identical properties. Therefore, grades should not be interchanged without performance equivalency ascertainment.
  • When preparing carbomer gels, powders should first be dispersed into vigorously stirred water, taking care to avoid the formation of agglomerates.
  • The dispersion should then neutralized by the addition of a suitable base.
  • Use granulated grades to reduce dusting issues during manufacturing.
  • Carbomers can easily be added to emulsions by addition to the oil phase prior to emulsification.
  • Adding electrolyte or small amounts of acid to the water phase prior to Carbomer addition significantly improves its dispersion by reducing solution viscosity. Up to 5% dispersions of Carbomer in water can typically be made with this approach.
  • Agitation of the dispersion should be done carefully and gently with a broad, paddle-like stirrer to avoid introducing air bubbles.
  • The viscosity of gels is significantly reduced at pH values less than 3 or greater 9, or in the presence of strong electrolytes.
  • Suitable neutralising agents include amino acids, potassium hydroxide, sodium bicarbonate, sodium hydroxide, and organic amines such as triethanolamine.
  • One gram of carbomer is neutralized by approximately 0.4 g of sodium hydroxide.
  • A number of manufacturers have introduced grades to overcome the challenges of dispersing powders in aqueous solvents, e.g Lubrizol’s Carbopol Ultrez.
  • Gels rapidly lose viscosity on exposure to UV light. To minimise this add a suitable antioxidant.

Leading Manufacturers of Carbomer Excipients

Recommended Carbomers for Pharmaceutical Formulations

  • Ultrez 30 (Lubrizol) has been shown to exhibit better electrolyte tolerance than other grades of Carbomer.
  • Ultrez 10 (Lubrizol) is a universal carbomer for broad applications. A 5% dispersion of Ultrez 10 exhibits viscosities in the 50 – 55 MPa s range.
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