David R. Schoneker is chairman of the International Pharmaceutical Excipients Council of the Americas. He also is director of global regulatory affairs at Colorcon.

David R. Schoneker

Titanium dioxide (also known as E171 or TiO

) has a long history of safe use across many global industries with several applications in paints, cosmetics, medicines, and food. TiO

 has recently been banned for use in foods and dietary supplements in Europe, and there is a potential that TiO

 could also be banned in pharmaceuticals in the European Union (EU) as early as 2025. The EU is currently evaluating an extension of the E171 ban to pharmaceuticals, and the impact of the potential ban would have serious consequences for the availability of many drugs for European patients.

The European Food Safety Authority (EFSA) re-evaluated the safety of TiO

 (E171), and although there were no studies showing direct interaction of E171 with DNA, EFSA concluded in May 2021 that a genotoxicity concern could not be ruled out and that E171 can no longer be considered safe in food (1). A ban on its use in foods was then quickly proposed by the European Commission (EC).

Read this article in the Quality and Regulatory Sourcebook 2023

David R. Schoneker is the president/owner/consultant at Black Diamond Regulatory Consulting, LLC.

When referring to this article, please cite it as D. Schoneker, "How Banning TiO

Pharmaceutical Technology's Quality and Regulatory

Articles

The impact of the potential ban would have serious consequences for the availability of many drugs for European patients.

How Banning Titanium Dioxide Might Impact Pharma

) General Notices combined, it could be interpreted that API requirements apply to excipients. In 

 General Notices, an API equals the labeled entity plus impurities. Applying this logic to excipients, anything NOT the labeled entity would be an “impurity.” Most excipients are more complex and less well defined than APIs. The excipient name may not reflect its complete composition. The named entity may be a minor component. The other components may be essential for functionality. This article seeks to promote dialogue among stakeholders to facilitate consensus regarding this topic. 

Due to excipient diversity, including highly complex mixtures from animal, botanical, mineral, and/or synthetic sources, differing approaches to characterizing excipient properties may be required. More complex excipients, including excipients produced by biotechnological methods, may require extensive physico-chemical characterization to fully understand their composition.

Additives and Processing Aids in Pharmaceutical Excipients

Understanding Concomitant Components in Pharmaceutical Excipients

Excipients are a diverse group of materials, which are used for a vast range of available drug products. Excipients intended for use by different routes of administration may require different understanding of the composition profile. Excipient manufacturers should seek to establish how their ingredients will be used. However, in commerce, this information is not always available from or shared by the user.

IPEC-Americas and IPEC Europe have published an 

, which describes the complex nature of excipients (1).  There are many excipient types, which have different compositional profiles. These include standard excipients, sometimes referred to as conventional or traditional excipients, mixed excipients, and co-processed excipients.

The excipient composition profile may be defined as a description of the components present in a typical excipient lot produced by a given manufacturing process. The main components of an excipient are those, which in most cases; contribute to the excipient being able to perform its intended function within the drug product(s) in which it is used (also known as “nominal” components). Other necessary components also may be present (i.e., concomitant components, additives, and processing aids). Unreacted starting materials, by-products, degradants, and residual solvents also may be present as a direct result of the excipient’s manufacturing process. These components may arise at different stages in excipient processing (

) and are considered part of the excipient composition profile. 

Finally, contaminants may be present (i.e., substances not directly resulting from the excipient manufacturing process [synthesis and/or purification], but as a consequence of extraneous factors such as personnel, equipment, packaging, other products, etc.). Contaminants would not be regarded as part of the composition profile; however, they should be controlled through good manufacturing practices (GMPs). 

As excipients are used typically without further purification, excipient manufacturers should identify and set appropriate limits for components as appropriate. These limits should be based on appropriate safety data, limits described in official compendia, or other requirements and sound GMP considerations. Manufacturing processes should be adequately controlled to ensure that undesirable components do not exceed established limits. 

For many excipients, classifying and quantifying all components may not be possible. Composition-related methods and specifications should be justified. There are many traditional, well-established (qualified by use) excipients for which it is neither feasible, nor necessary, for safety purposes to identify all components. Evaluating (re-evaluating) their safety, unless scientific evidence becomes available that suggests otherwise, is generally unnecessary. Where feasible, generating composition profiles should involve each component’s identification, classification, and quantification (expressed as a range). If unidentified, an appropriate qualitative description such as a chromatographic peak retention time should be made available. A reasonable reporting threshold is available from the International Council for Harmonization (ICH) Q3A (R2) guideline (2).

In addition to the “nominal” component, excipient components may comprise the following:

Unreacted starting materials such as monomers in polymerization

Reaction by-products (e.g., isomers and side reactions)

Raw material components (especially for naturally sourced materials).

Establishing an excipient composition profile 

Where possible, excipient manufacturers should establish composition profiles where the main excipient components are identified and their normal concentration variability determined. Acceptable limits, where required, should be based on a risk assessment using sound science. It is typically not necessary to have limits for all components in the composition profile, but the profile should be understood. Limits should only be established when justified by risk assessment to address safety and/or customer-specific concerns. 

An excipient composition profile evaluation should be performed by the excipient manufacturer using their manufacturing process knowledge and understanding, which may lead to identifying associated potentially undesirable components. Excipient components (i.e., main/concomitant components, additives, processing aids, and undesirable components) should be identified and quantified using suitable analytical techniques, wherever possible. Appropriate analytical methods may be compendial or suitably qualified manufacturer-specific methods. The materials used for composition profile development should be representative of the excipient, and sampled in a manner consistent with that used for lot release by the quality control unit (i.e., same sampling technique and sampling point(s) in the manufacturing process). 

The United States Pharmacopeial Convention (USP) merged the General Notices for both the 


) in early 2000. In effect, this means that the same General Notices restrictions apply to both APIs and excipients. It could, therefore, be argued that API requirements also apply to excipients. In the General Notices, an API equals the labeled entity plus impurities. If the same logic is applied to excipients, anything other than the labeled entity could be considered an “impurity.”
	
The current 

“impurity” or “concomitant component” definitions only apply to drug substances and drug products but not excipients. Similarly, ICH addresses impurities in new drug substances and drug products as follows: 

Any component of the new drug substance that is not the chemical entity defined as the new drug substance (2)

Any component of the new drug product that is not the drug substance or an excipient in the drug product (3)

Any component present in the intermediate or API that is not the desired entity (4). 

	These definitions do not specifically apply to excipients and cause confusion when inappropriately applied to them. Excipient-specific definitions are therefore required and should be included in future issues of the 

The situation regarding excipients is put forth in an excerpt from the International Pharmaceutical Excipients Council (IPEC) Composition Guide:
	“For excipients, the situation is more complex as they are frequently multicomponent, and their composition may be less well defined. Their functionality may be dependent on the presence of components other than the labeled entity. The definition of the term ‘impurity’ as used above for drug product and/or drug substance is thus misleading when applied to excipients. To distinguish these components from true impurities, the appropriate term for describing excipients should be ‘minor component’ or ‘concomitant component’ (e.g., the water of crystallization in magnesium stearate required for optimum lubricant effectiveness)” (1). 

Advances in analytical technologies can give excipient manufacturers, users, and regulators more quantitative excipient composition detail, but not necessarily increased understanding of excipient functionality. Increased analytical capabilities are to be encouraged, but, taken out of context, can cause confusion and inappropriate or counterproductive actions by users and regulators.

Significant differences between APIs and excipients

FDA defines an “Active Ingredient” (here used interchangeably with the term API) as “any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals” (5). FDA does not have an official definition for “excipient,” but rather uses the term “Inactive Ingredient,” which they define as “any component of a drug product other than the active ingredient” (6).

 General Chapter <1078> Good Manufacturing Practices For Bulk Pharmaceutical Excipients defines an excipient as “Any substance, other than the active pharmaceutical ingredient or drug product, that has been appropriately evaluated for safety and is included in a drug delivery system to aid the processing of the drug delivery system during manufacture; to protect, support, or enhance stability, bioavailability, or patient acceptability; to assist in product identification; or to enhance any other attribute of the overall safety and effectiveness of the drug delivery system during storage or use” (7). 

Some of the general differences between APIs and excipients are summarized (

). Exceptions exist (e.g., in the case of small-molecule synthetic API-like excipients and naturally derived APIs such as digitalis and fish oil). 

In the case of APIs, the labeled entity is generally well-defined and quantified by assay to ensure purity. Other components are considered impurities, that is, the balance of 100% minus the assay. For excipients, the labeled entity can be nominal, and there is not always a specific assay (e.g., microcrystalline cellulose). The labeled entity itself may not even be the predominant component. For example, stearic acid 50 NF can contain as little as 40 wt. % stearic (octadecanoic) acid and as much as 50 wt. % palmitic (hexadecanoic) acid.  The latter major component is a concomitant component, not an impurity. There may also be up to 10 wt. % other components. The labeled entity may also be nominal for polymeric excipients, usually reflecting an average molecular weight.

, “The presence of any unlabeled other impurity in an official substance is a variance from the standard if the content is 0.1% or greater. The sum of all other impurities combined with the monograph-detected impurities may not exceed 2.0% unless otherwise stated in the monograph” (8). 

This statement is not appropriate for excipients. If a distinction is not made between concomitant components, additives, residual processing aids, and impurities, there is likely to be confusion regarding excipient applicability of specific impurity identification and quantification requirements typical for APIs. This could encourage attempts to set inappropriate specifications by users and result in excipient shortages, if the specifications are outside the process capability of excipient manufacturers.  

The authors propose that the following excipient-specific definitions be adopted by 

Concomitant component-A substance found in an excipient that is not the intended chemical entity, may be necessary for assuring the proper performance of the excipient in its intended use, and is not an impurity or a foreign substance. (Formerly referred to as minor component) (9) 

Additives-A substance added to the excipient to improve or maintain a characteristic such as a preservative, flow agent, antimicrobial, etc. (9)

Processing aids-A material added to a manufacturing step for the purpose of facilitating the completion of that step or subsequent step (9) 

Impurity-An undesirable material found in an excipient as a consequence of the raw materials, excipient manufacturing process, or excipient degradation (9).

Excipient composition example-Polyethylene Glycol 600

Excipients can be complex mixtures of substances, some or all of which may affect functionality.

Polyethylene glycol 600 NF (PEG 600), which is a complex mixture of the tridecamer (mol. wt. 590), other oligomers (concomitant components), and impurities, is a good example. It is by no means the only example. Other examples include polymeric excipients, some excipients derived from natural fats and oils, and mineral ores. 

Polyethylene glycols are polymers of ethylene oxide and water. In the NF, the number after polyethylene glycol or PEG indicates the mean molecular weight of the polymer. PEG 600, which has been safely used as an excipient for many years, is used (among other applications) in hard and soft gelatin capsule formulations to enhance active substance solubility (10). 

While the “600” nomenclature indicates mean molecular weight, other higher and lower molecular weight oligomers present impact performance. In addition, the specified impurities ethylene glycol and diethylene glycol must not jointly exceed 0.25 wt. %. A suitable antioxidant (additive) may also be present. The antioxidant would be a stabilizer and thus an additive, not an impurity.

Historically, polyethylene glycol grades were specified by viscosity, but their multicomponent nature is now revealed by modern chromatographic techniques. The Cleaver chromatogram (11) shows multiple oligomers present, most of which are present at levels well in excess of 0.1 wt. %, and the sum of which exceed 2 wt. %. Given the current impurity limits and “definition” put forth in the 

 General Notices, these oligomers could be construed as “impurities.”

However, since finished pharmaceutical formulations using PEG 600 have been based on PEG 600 functionality, which is predicated on the presence of the oligomers shown in the chromatogram, the effect of removing all oligomers except the tridecamer is unknown, even if it were possible to do so. The presence of these oligomers may provide essential contribution to PEG 600 drug delivery properties.  In addition, their presence does not pose a health or safety risk. 

In the case of ethylene glycol and diethylene glycol, both of which could be present in PEGs, there is a clear need to set limits for the “undesirable substances” (impurities) because they are toxic to humans and animals. 

Communication disclosure methods needed for additives and processing aids 

IPEC-Americas recognizes the need to provide appropriate details regarding excipient composition. There are excipients in approved medicines, which contain undeclared additives or residual processing aids and yet have a long history of use. Given the large number of excipients involved, and the much greater number of pharmaceutical products potentially affected, there is a need for IPEC-Americas, FDA, and USP to collaborate in developing a path forward and avoiding potential drug product shortages. There has not been a consistent approach to excipient additives and residual processing aids disclosure, even though these ingredients have been used safely for many years. However, it must also be recognized that the presence of certain other components in excipients may present intellectual property issues (trade secrets and know-how).  A mechanism is required, and should be developed, for sharing confidential information with FDA and without direct disclosure of the identity and level of additive or residual processing aids to users.

For an excipient having a monograph in the 

, there are issues with such additives and residual processing aids. USP General Notices 5.20 Added Substances (12) states as follows:

“5.20. Added Substances  “Added substances are presumed to be unsuitable for inclusion in an official article and therefore prohibited, if: (1) they exceed the minimum quantity required for providing their intended effect; (2) their presence impairs the bioavailability, therapeutic efficacy, or safety of the official article; or (3) they interfere with the assays and tests prescribed for determining compliance with the compendial standards.
	
“The air in a container of an official article may, where appropriate, be evacuated or be replaced by carbon dioxide, helium, argon, or nitrogen, or by a mixture of these gases. The use of such gas need not be declared in the labeling.

“5.20.10. Added Substances in Official Substances 

“Official substances may contain only the specific added substances that are permitted by the individual monograph. Such added substances shall not exceed the quantity required for providing their intended effect. Where such addition is permitted, the label shall indicate the name(s) and amount(s) of any added substance(s).”

The presence of undeclared additives and processing aids conflicts with General Notices requirements. A mechanism is needed for confidential disclosure of the presence of additives and residual processing aids without required labeling as specified currently by 

IPEC-Americas has submitted a background document on this issue to FDA and has requested a meeting to discuss possible disclosure mechanisms for these ingredients and potential changes needed in the 

Many excipients are multi-component with well-established safety profiles. Components other than the labeled entity may also impact excipient performance. For excipients, concomitant components, additives, and residual processing aids should be distinguished from impurities in terms of undesirable substances, which should be absent or controlled for safety reasons. 

The current API-specific requirements put forth in the USP 40-NF 35 General Notices are not appropriate for excipients. It is therefore recommended that USP and FDA take the following actions:

Revise General Notices 5.60.10 and 5.20.10 to address excipient requirements by incorporating the aforementioned proposed definitions. 

Include excipients in the list of exceptions in the Other Impurities requirements in 5.60.10.

Provide excipient manufacturers with a means to confidentially communicate additives and residual processing aids presence to regulators without public disclosure.

Q3A(R2) Impurities in New Drug Substances

, Current Step 4 Version (ICH, 2006).
3. ICH, 

, Current Step 4 Version (ICH, 2006).
4. ICH, Q7 

Good Manufacturing Practice Guide for Active Pharmaceuticals Ingredients

, Current Step 4 Version (ICH, 2000).
5. FDA, 

, May 14, 2015.
7. USP, “General Chapter <1078> Good Manufacturing Practices For Bulk Pharmaceutical Excipients,” 

 [Official May 1, 2017] (USP, Rockville, MD, 2015) 
8. USP, 

 [Official May1, 2017], p. 5.60.10 (USP, Rockville, MD, 2015).9. IPEC, “General Glossary of Terms and Acronyms,” Arlington, 2014.
10. Dow Corporation, “

,” year unspecified [online].
11. G. Cleaver, “Sensitive Analysis of Oligo Polyethylene Glycol by Reversed Phase HPLC with ELSD Application Note,” Agilent Technologies, Inc., UK, 2011.
12. USP, 

 [Official May 1, 2017], p. 5.20.10 (USP, Rockville, MD, 2015).

When referring to this article, please cite it as B. Carlin et al., "The Real Complexity of Excipient Composition," 

This article seeks to promote dialogue among stakeholders to facilitate consensus regarding requirements for excipients. 


The Real Complexity of Excipient Composition

Making drug-embedded matrix tablets through the direct compression of a blend of drug, retardant material, and additives is one of the simplest formulation approaches. The inclusion of polymeric materials in a matrix system is a common method of modulating drug release (1). Drug-release retarding polymers are the key performers in matrix systems. Various polymers have been investigated as drug-retarding agents, each presenting a different approach to the matrix system. Based on the features of the retarding polymer, matrix systems are usually classified into three main groups: hydrophilic, hydrophobic, and plastic. Hydrophilic polymers are most suitable for retarding drug release, and interest is growing in using these polymers in sustained drug delivery (2–4). 

In India, natural gums and mucilage are well known for their medicinal use. Natural gums and mucilage are preferred to semisynthetic and synthetic excipients because of their lack of toxicity, low cost, availability, soothing action, and nonirritant nature (5–8). Many natural materials are studied for use in sustained-release tablets. These materials include: guar gum (9), ispaghula husk (10), olibanum and its resins (11), cross-linked high amylose starch (12), 

 (slippery elm mucilage) (13), pectin (14), 

dry plant extract (15), galactomannon from 

 (20), Tamarind seed gums (21), and gum copal and dammar (22).   

has not been explored as a pharmaceutical excipient. 

family is also known as the shoe-flower plant, China rose, and Chinese hibiscus. The plant is available in India in large quantities, and the leaves contain mucilage (23, 24). The leaves are used in traditional medicines as emollients and aperients to treat burning sensations, skin disease, and constipation (25). The plant contains cyclopropanoids, methyl sterculate, methyl-2-hydroxysterculate, 2-hydroxysterculate malvate, and β-rosasterol. Mucilage of 

 contains L-rhamnose, D-galactose, D-galactouronic acid, and D-glucuronic acid (26). The leaves contain carotene (7.34 mg/100 g of fresh material) and are used as cattle feed (27). The leaves also contain moisture, protein, fat, carbohydrate, fibers, calcium, and phosphorus (28). 

The objective of this study was to extract mucilage from the leaves of 

 and examine the various pharmaceutical properties of the dried mucilage to assess its functionality as an excipient. Specifically, the study  evaluated the physicochemical properties and examined the effect of polymer blends on the rate and kinetics of diclofenac sodium released from matrix tablets.  

Diclofenac sodium is a potent nonsteroidal anti-inflammatory drug. Diclofenac sodium rapidly dissolves in intestinal fluid, reaches its maximum blood concentration (

max) within 30 min, and is metabolized mainly by hepatic hydroxylation and subsequent conjugation (29). In healthy human volunteers, the mean plasma clearance of diclofenac sodium was 16.0 L/h, and the mean elimination half-life of the terminal phase was 1.2–1.8 h (30). To reduce gastrointestinal irritation, a common problem with all nonsteroidal anti-inflammatory agents, effective enteric-coated dosage forms have been developed. Food delays the absorption of the drug, which  causes a nonreproducible pharmacokinetic profile, and the drug has no immediate therapeutic effect (31).  

Drug release from hydrophilic matrices is a complex interaction between dissolution, diffusion, and the erosion mechanism. In this study, the drug-release mechanism was evaluated for diclofenac sodium tablets prepared with highly hydrophilic mucilage from the leaves of

  full factorial design was carried out to evaluate the effect of certain variables such as the amount of mucilage and diluent. Further studies were performed using water uptake, the mass loss of pure mucilage, and the matrix tablet containing the drug and mucilage. A stability study for an optimized batch was performed for three months. 

Diclofenac sodium was received as a gift from Beacon Pharmaceuticals (Ahmedabad, India). The leaves of 

 were collected from the medicinal garden of the C.K. Pithawala Institute of Pharmaceutical Science and Research in Surat, India. Guar gum 

  (IP) grade, ispaghula husk, sodium carboxymethyl cellulose IP, lactose IP, talc IP, and magnesium stearate IP were received from Atul Chemicals (Anand, India). All other solvents and chemicals were of analytical-reagent grade. Deionized double distilled water was used throughout the study. 

 were collected, washed with water to remove dirt and debris, and dried. The powdered leaves were soaked in water for 5–6 h, boiled for 30 min, and kept aside for 1 h for complete release of the mucilage into water. The material was squeezed from an eight-fold muslin cloth bag to remove the marc from the solution. Acetone was added to the filtrate to precipitate the mucilage in a quantity of three times the volume of the total filtrate. The mucilage was separated, dried in an oven at a temperature  < 50 °C, collected, dried-powdered, passed through a sieve (number 80), and stored for further use in desiccators (32). 

Physicochemical properties of dried powdered mucilage. 

Dried- powdered mucilage was studied for percentage yield, particle size, mass loss on drying, viscosity, swelling index, bulk density, angle of repose, and compressibility.  

 The microscopic method was used (in triplicate) to determine the particle size of the dried mucilage.  

 The mass loss on drying was determined for an appropriate quantity of dried mucilage at 105 °C for 2 h in a hot-air oven. 

 The study was carried out in a 100-mL stoppered graduated cylinder. The initial bulk volume of 1 g  of dried mucilage was measured, and water was added in sufficient quantity to yield a 100-mL uniform dispersion. The sediment volume of the swollen mass was noted after 24 h in storage at room temperature. The swelling ratio was calculated by determining the ratio of the swollen volume to the initial bulk volume. The swelling ratio was evaluated in distilled water, simulated gastric fluid (0.1 N HCl), and phosphate buffer (pH 6.8) (33). 

  Rheological studies of dried mucilage were carried out using various concentrations of solution (0.1–0.5% weight/volume (w/v) in distilled water. The viscosity was measured using an Ostwald viscometer and compared with the viscosity of sodium carboxymethylcellulose.  

 A preweighed and presieved quantity of dried mucilage was poured into a graduated cylinder, and the volume recorded. The cylinder was tapped until the powder bed volume reached a minimum value, and the tapped volume was recorded. The bulk and tapped densities were calculated. Carr's index and Hausner ratio. Carr's index and Hausner ratio were calculated from the bulk and tapped densities.  

  The angle of repose (θ) was determined using the fixed-height funnel method and calculated as follows:  

is the radius of the powder heap. Comparisons were made between dried mucilage, guar gum, and ispaghula husk. 

Preparation of diclofenac sodium tablets. 

The required quantities of diclofenac sodium and dried mucilage powder (sieve number 80) were physically admixed. Lactose was included in the nine batches of factorial design. The powder blend was lubricated with 1% w/w talc and 2% w/w magnesium stearate. Lubrication was performed in a glass jar for 2 min. Each tablet contained 100 mg of the drug. The tablets were prepared by direct compression on a rotary tablet press (Rimek II, Karnavati Engineering, Ahmedabad, India) and fitted with concave punches of 9 mm in diameter. The turret was rotated at a fixed speed of 30 rpm (34). 

Hardness was determined by using the Monsanto hardness tester, and friability was evaluated as the percentage weight loss of 20 tablets tumbled in a friabilator (Model EF2, Electrolab, Mumbai, India) for 4 min at 25 rpm. The tablets were dedusted, and the loss in weight caused by the fracture or abrasion was recorded as the percentage friability.  

 The weight-variation test was performed. Twenty tablets were weighed individually, and the average weight was calculated.  

The drug-release study was carried out using an USP XXIII paddle apparatus at 37 ± 0.50 °C at 50 rpm using 900 mL of distilled water and phosphate buffer (pH 6.8) as the dissolution medium (n = 5). A 5-mL sample solution was withdrawn at predetermined time intervals, filtered through a 0.45-μm membrane filter, diluted suitably, and analyzed spectrophotometrically at 276 nm using a UV-visible double-beam spectrophotometer (Shimazdu-UV 1700, Shimazdu, Kyoto, Japan). Equal amounts of fresh dissolution medium were replaced immediately after withdrawing a test sample. The percentage of drug that dissolved at different time intervals was calculated using a regression equation generated from the standard curve. Drug release from the optimized batch (HL6) and a market preparation of the drug were studied in distilled water. 

  randomized full factorial design was used. Two factors were evaluated, each at three levels, and experimental trials were performed at nine possible combinations. The ratio of mucilage (

) were selected as independent variables. The time required for 80% drug dissolution (

) and percentage drug released in 60 min (

Hydration capacities and erosion studies. 

  Erosion and water uptake of the formulated tablets were determined under conditions identical to those previously described for dissolution testing. Water uptake and mass loss were determined gravimetrically according to the following equations (35):   

Three tablets were used per time point. At predetermined times, the ring-mesh assemblies supporting the partially hydrated tablets were carefully removed, and the tablets were lightly blotted with tissue paper to remove excess surface water. After determining the wet weight, the tablets were dried at 70 °C for one day before reweighing to determine the remaining dry weight. The test was performed at speeds of 50 and 100 rpm. Placebo tablets consisting of pure mucilage were tested in the same way. All studies were performed in triplicate. 

Radial and axial swelling of the tablet. 

 The initial diameter and thickness of the tablet were measured, and the tablet was  kept in dissolution media. The increase in diameter and thickness was measured at various time intervals. To evaluate the relation, the equilibrium degree of swelling (

) was calculated from the radial and axial swelling ratio using the following equation: 

 drug release, the stability study of the best formulation (HL6) was carried out at 40 °C and 75% relative humidity in a humidity oven. Samples were withdrawn after a three-month interval, and 

Various physiochemical characteristics of the extracted mucilage from 

 were investigated. The percentage yield was 15%, and the average particle size was 180 μm. The mass loss on drying indicated the amount of moisture present in the material that was available to interact with other material. For dried mucilage, the mass loss on drying was 10.61%. The swelling ratio of mucilage was 9 in distilled water, 10 in simulated gastric fluid (0.1 N HCl), and 9 in phosphate buffer (pH 6.8). The authors  concluded that the swelling of mucilage is pH-independent, and the mucilage is nonionic. 

Table I:  Rheological data of  dried-powdered mucilage and sodium carboxymethylcellulose (CMC). 

The viscosity of the extracted dried mucilage was compared with that of semisynthetic polymer sodium carboxymethyl cellulose (see Table I). When dried mucilage concentration exceeded 0.2% w/v, the viscosity was very difficult to measure with the Ostwald viscometer. The dried mucilage had higher viscosity than the sodium carboxymethylcellulose. 

Table II:  Flow properties of dried-powdered mucilage and other gums.  

The flow properties and compressibility of the dried mucilage, including bulk and tapped density, Carr's index, Hausner ratio, and the angle of repose were assessed and compared with those of guar gum and ispaghula husk (see Table II). The angle of repose of a powder provides an insight into the magnitude of the cohesiveness of the powder and hence, its flowability. Mildly cohesive powders have angles of repose between 40° and 60° when measured by standard methods. Dried mucilage has an angle of repose of 27.83°. Guar gum and ispaghula husk have an angle of repose of 42.27°and 38.79°, respectively. From these results, the authors infer that the dried mucilage powder was less cohesive and had superior flow property. The Hausner ratio previews the degree of densification that could occur during tableting: the higher the ratio, the greater the propensity of the powder to densify. This phenomenon may produce tablets that lack uniformity of weight and content. The dried mucilage has excellent flow properties compared with those of guar gum and ispaghula husk. Dried mucilage, therefore, has flow properties suitable for use in a direct-compression formulation. 

Table III: Formulation of tablets and Y60, Y300, and t80 of preliminary batches. 

The average crushing strength of the prepared tablets was 4.8 kg/cm

 , a value which shows good strength. The friability was < 1% (i.e., between 0.75 and 0.91%). Tablets prepared from dried-powdered mucilage that passed the standard for uniformity in weight indicate homogenous drug content. These results show that tablets prepared from dried-powdered mucilage can be used as a directly compressible vehicle because of good hardness, low friability, and tablet-weight uniformity.  

Table IV: Formulation and dissolution characteristics of batches in a 32 full factorial design. 

Table III shows the composition of the preliminary batches (L1 to L3) and the results of their dissolution studies. Table IV shows the composition of the nine batches of the factorial design and the results of their dissolution studies. When the dissolution study of the preliminary batches was performed, the complete drug release was obtained within 9, 10, and 11 h with different proportions of mucilage and 100 mg of diclofenac sodium (see Table III). The authors concluded that mucilage is suitable as a sustained-release matrixing agent for a diclofenac sodium tablet. Four criteria were established for the desired drug-release profile:   

A release of 20–25% of the drug within the first hour.

Prolonged drug release of the remaining drug followed during 12 h, preferably at a relatively constant rate

The time to release 80% of the drug was 490 < 

  full factorial design was constructed to study the effect of dried mucilage powder (

) on the drug release of the diclofenac sodium tablets. The dependent variables chosen were 

 (i.e., the percentage of drug released in 60 and 300 min, respectively and the time to release 80% of the drug). The following statistical model incorporating interactive and polynomial terms was used to evaluate the response: 

  is the arithmetic mean response of the nine runs, and b

is the estimated coefficient for the factor 

) represent the average result of changing one factor at a time from its low to high value. The interaction terms (

) show how the response changes when two factors are simultaneously changed.  

 values for the nine batches (HL1 to HL9) showed a wide variation: 22.38 to 34.00%, 52.75 to 69.33%, and 388 to 547 min, respectively. The data (see Table IV) clearly indicate that the values are strongly dependent on the selected variables. The fitted equation relating the response 

 to the transformed factor is shown in equations 6–8:  

The values of the correlation coefficient were 0.9879, 0.9831, and 0.9870, respectively, indicating a good fit. Equations 6 and 7 may be used to obtain a reasonable estimate of the response because a small error of variance was noticed in the replicates. The polynomial equation can be used to draw conclusions after considering the magnitude of the coefficient and the mathematical sign it carries (i.e., positive or negative). The data demonstrate that both factors (

 of the coefficient also suggests that the interaction between 

Batches HL3 and HL6 met the set criteria of 

, < 25%. Batches HL3, HL5, HL6, and HL9 met the set criteria of 

 < 60%. Batches HL6 and HL9 met the set criteria of 

  between 490 and 590 min. Among the entire batches, only HL6 fulfilled all the selection criteria, which included prolonged drug release of the remaining drug over 12 h. Batch HL6, therefore, was selected as the optimized batch. 

The dissolution data of batch HL6 were compared with the ideal release profile using f

value of 87.86 indicates that the release profile of batch HL6 was comparable with the ideal batch. A value of f

 ≥ 50 is necessary for similarity in dissolution profile at 10% difference. Table V shows the results of multiple linear regression for the response 

  indicate good fit. The drug release of the best batch HL6 was also conducted in phosphate buffer (pH 6.8). The dissolution data of batch HL6 in distilled water were compared with the dissolution data in phosphate buffer (pH 6.8). An f

 of 89.68 indicated that the release profile of batch HL6 in distilled water and phosphate buffer were comparable. Lastly, the dissolution of batch HL6 was compared with the market preparation of the drug in distilled water. The dissolution data of both were compared using f

 of 90.48 indicates that the release profile of batch HL6 and the market preparation of the drug were comparable. 

Natural gums and mucilage are biocompatible, cheap, readily available, and represent a potential source of excipients. The authors examine the functionality of mucilage extracted from the leaves of Hibiscus rosa-sinensis Linn as an excipient in a sustained-release tablet formulation.

Assessing Hibiscus rosa-sinensis Linn as an Excipient in Sustained-Release Tablets

			As China emerges as a significant supplier of pharmaceutical ingredients, it must assure other countries of the safety of its excipients. China's State Food and Drug Administration (SFDA) intends to revise its excipient-control regulations to protect consumers at home and abroad. The agency has begun to meet with international trade organizations such as the International Pharmaceutical Excipients Council (IPEC) to hear industry's concerns. The author describes the contacts between SFDA, IPEC, and other international bodies. The article explains what SFDA has learned and how it may adjust its regulations for the future.			

As China's role in the global pharmaceutical market increases, the Chinese State Food and Drug Adminstration (SFDA) and many China-based pharmaceutical manufacturers and excipient producers are beginning to collaborate with their international counterparts on excipient-control issues. Compliance with appropriate good manufacturing practices (GMPs) throughout the entire excipient distribution supply chain and an understanding of international regulatory and pharmacopeial excipient controls are critical components for ensuring that pharmaceutical excipients are safe and of acceptable quality. The recent tragedies related to contaminated glycerin and other products sourced from China underscore the need for safe excipients. 

China's proposed new license requirements for the manufacture and use of excipients

During the last two years, several regulatory developments related to the manufacture, importation, and use of excipient ingredients in China have taken place. In the past, China has required certain types of licenses for the manufacture and use of excipients in the country. Recent proposed changes to the registration requirements, however, could significantly affect the future availability of excipients produced in China for the country's domestic market and for export. 

SFDA issued new Drug Excipients Registration Application Materials requirements on June 21, 2005. The regulation covered various excipient-registration requirements, including those for imported excipients. In December 2005, SFDA revised these requirements and proposed a new set of regulations to control excipients used in products marketed in China. The regulations would establish new GMP and manufacturing rules for excipients produced in China and new requirements for obtaining an import license for pharmaceutical excipient ingredients that are produced outside of China. 

To obtain an import license under these proposed regulations, excipient manufacturers would be required to provide additional detailed information concerning the manufacture of their pharmaceutical ingredients and specific additional data to substantiate the excipient's safety for its intended use. The regulations would apply to new excipients and commonly used compendial excipients that have been used for years in China. The level of data and information that the proposed regulations would require significantly exceeds what has been previously required in China. The requirements also exceed the amount of information generally required in other major market countries, especially for compendial excipients. The proposed regulation would require the pharmaceutical manufacturer to obtain a copy of the license for each excipient in its formulation from each of its excipient suppliers to support the use of these excipients in drug products made in China. 

Proposed regulations for excipients that are produced domestically in China are similar to those for excipients that are imported into China from foreign manufacturers. Domestic excipient manufacturers must meet a higher quality and GMP standard than China has typically required in the past, and they must supply more information to SFDA about their products and processes. In addition to the current requirement of being registered with SFDA, excipient manufacturers would also be routinely inspected for GMP compliance. The regulations as applied to domestic Chinese excipient manufacturers will significantly affect these domestic excipients' availability and cost. Additionally, the proposed import license requirements would potentially increase costs significantly for all multinational excipient companies who intend to supply their excipients to China. The requirements could cause some companies to stop supplying the Chinese market because of cost and intellectual-property concerns. 

The licensing requirements for imported excipients are somewhat different from those for domestic Chinese manufacturers and contain many criteria that are especially difficult for many excipient manufacturers to meet (see sidebar, "SFDA's proposed requirements for obtaining an import license"). 

SFDA proposed requirements for obtaining an import license			

In the past, excipients used in China were regulated in the same manner as drugs or active pharmaceutical ingredients (APIs). The domestic implementation of licensing requirements was somewhat inconsistent for excipients, however. SFDA proposes to separate the regulation of excipients to facilitate improved control of quality for both domestic and imported excipients. The goals of their proposed excipient regulations are to improve the quality of excipients, minimize safety risks, and to align SFDA regulations with international standards. In developing the excipient regulations, SFDA has proposed to use the basic principles of its drug regulations as a foundation for excipient regulation. The proposed regulations, however, do not recognize the significant differences between excipients, APIs, and drug products in terms of typical international regulatory requirements. 

The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas), a trade association of manufacturers of excipients and drug products, has led an industry coalition representing excipient producers and users that works with SFDA to clarify the requirements for obtaining a Chinese import license and to assist SFDA in achieving its goal of improved excipient quality and safety. IPEC-Americas representatives have attended meetings with SFDA to discuss the differences between excipient regulations in the US, Europe, and Japan and the proposed excipient regulations in China. A coalition coordinated by the International Pharmaceutical Excipients Council (IPEC) has requested several changes to the proposed regulations to achieve better harmonization with international standards and requirements. The IPEC Coalition includes IPEC Americas, IPEC Europe, and the Japanese Pharmaceutical Excipients Council (JPEC). 

The IPEC Coalition, in collaboration with the US Department of Commerce, presented the industry's concerns to SFDA at a meeting of the Joint Commission on Commerce and Trade (JCCT) in March 2006. This discussion, along with several follow-up meetings in April 2006, resulted in a fairly favorable first step toward improved excipient regulation. The IPEC Coalition and other participants provided SFDA with information about the regulation of excipients in the US, Europe, and Japan and identified problem areas in SFDA's proposed regulations that would significantly affect both excipient manufacturers seeking import licenses and pharmaceutical companies who would use these materials in China.  

SFDA informed the participants that, unlike in most developed countries where pharmaceutical manufacturers essentially regulate their use of excipients with limited regulatory agency oversight, China's government must be responsible for excipient quality. SFDA believes that many Chinese pharmaceutical manufacturers do not have good systems in place to properly qualify excipient suppliers and control excipient quality. SFDA believes that the government must step in to provide adequate protection to Chinese consumers. Accomplishing this goal may require some type of excipient licensing system, according to the agency. 

On the other hand, SFDA wants to draft regulations based on appropriate international standards and does not want to impose unrealistic regulations on imported excipients. The agency expects to be able to review the same type of information used to establish excipient quality and safety that is required by international regulatory authorities during the drug-registration process. Since most regulators outside China do not require significant detailed information to be submitted for compendial excipients, SFDA may relax its proposed license requirements for these types of materials. 

SFDA and the Coaltion agreed that detailed safety and manufacturing information should be required for the licensing of new excipients and that the regulations should reflect the different needs for evaluating compendial excipients versus new excipients. 

SFDA stated that it will study the excipient GMPs and other guidelines provided by the IPEC Coalition to further revise its excipient regulations. SFDA expressed a desire to learn from other countries' success and to use that experience to develop excipient regulations for China. SFDA also noted that although the new excipient regulations have been proposed, no firm implementation date had been set, and that it was unlikely that they will be finalized until 2008. SFDA will use the time to carefully review and assess the documents supplied to them, as well as the various presentations made during its meetings with IPEC Coalition representatives. 

One outcome of the 2006 meetings was the recognition of the need to hold an excipient conference in China to discuss how excipients are regulated globally. Such a conference would facilitate SFDA's collaboration with industry for a mutually beneficial resolution of the licensing requirements. In 2007, the IPEC Coalition has continued to help SFDA develop excipient regulations that are science-based and achievable without causing undue regulatory burden that may result in some excipient manufacturers exiting the marketplace. 

IPEC–CCPIE excipient-control strategies conference

More than 150 people participated in an International Excipient Control Strategies Conference in Beijing on March 13–14, 2007. The conference was organized by the China Center for Pharmaceutical International Exchange (CCPIE), IPEC Americas, IPEC Europe, and the Japanese Pharmaceutical Excipient Council (JPEC), with help from the Research and Development-Based Pharmaceutical Association Committee (RDPAC) in China. The meeting attracted at least 30 SFDA division directors and other agency personnel, plus many Chinese and international excipient and finished-drug manufacturers. 

The conference was designed to provide the pharmaceutical and excipient industry, SFDA, and several major pharmacopeias an opportunity to interact on topics related to the control of excipients used in pharmaceutical products marketed in China and the rest of the world (see sidebar, "Goals of the International Excipient Control Strategies Conference"). 

Goals of the International Excipient Control Strategies Conference			

Speakers at the conference included Zhang Wei, director of SFDA's Department of Drug Registration; Wang Ping, deputy general secretary of the Chinese Pharmacopeia; Dr. Agnes Artiges, director of the European Pharmacopoeia; Dr. Kiyomi Ueno, director of the Japanese Pharmacopeia's standards division; Dr. Roger Williams, chief executive officer of the US Pharmacopeia (USP); and Dr. Catherine Sheehan, USP's director of excipients. Several industry speakers from IPEC member companies described how pharmaceutical excipients are evaluated for safety and controlled for quality throughout Europe, Japan, and the US. Song Ming Xian, director of the regulatory division of the Sichuan Provincial Food and Drug Division, summarized current SFDA excipient GMP regulations and described the need for a Chinese industry association dedicated to improving excipient quality. 

Zhang Wei, director general of SFDA's registration department, gave the opening speech, which provided interesting information about what direction SFDA may take when it revises the draft excipient regulations. He provided his vision of how SFDA might regulate excipients in the future. 

In his speech, Wei addressed many of the issues that the IPEC Coalition had raised regarding SFDA's draft regulation, and he indicated that more flexibility is warranted. Wei recommended that the licensing requirements for the most common compendial excipients could potentially be eliminated and that a DMF-type system be established for premixed and coprocessed excipients. He stressed, however, that a detailed licensing system would need to be set up to control excipients intended for injections because of the high level of risks associated with these materials. 

SFDA's concepts regarding this regulation have changed significantly since the agency proposed its original draft. At that time, it appeared that the agency would publish a regulation that would create great difficulties for industry without benefiting consumers. The ongoing dialogue between the IPEC Coalition and SFDA seems to have influenced the debate over the regulations in a positive way. 

All the speakers described how excipients are controlled from various perspectives in each major market region. The excipient conference provided a valuable overview of global excipient regulations. 

After the conference, Wei reported that the expected redraft of SFDA's excipient regulations in China would be postponed until 2008 and that some changes might be based on comments made to the agency. 

IPEC discussed the formation of an industry-based excipient working group in China, which is currently being explored. IPEC proposes to organize an excipients organization in China that would be similar to other IPEC groups. Each group originally formed after a major excipients conference at which it became obvious that such a group would benefit the industry, pharmacopeias, regulatory agencies, and consumers. IPEC hopes to form an excipients working group in China in late 2007 and has continued working with SFDA since the March 2007 conference on excipient controls. 

IPEC Americas worked with the US Department of Commerce to enable SFDA to visit two excipient-manufacturing facilities and one API-manufacturing facility. SDFA representatives conducted visits during their trip to the Annual JCCT meeting in Washington, DC, on April 9–12, 2007. SFDA wanted to tour excipient and API facilities to see how US manufacturing facilities for excipients and APIs meet GMPs. The agency also wanted to understand how manufacturing processes for these materials are controlled in the US. 

As China emerges as a significant supplier of pharmaceutical ingredients, it must assure other countries of the safety of its excipients.