Hypromellose / Hydroxypropyl Methylcellulose / HPMC
What is Hypromellose (HPMC)?
Hypromellose (HPMC), also known as hydroxypropyl methylcellulose, is a chemically modified cellulose ether widely used as a pharmaceutical excipient. In pharmaceutical formulations, HPMC is used as a binder, film-forming and coating polymer, capsule material, thickening agent and, importantly, as a release-modifying polymer in hydrophilic matrix tablets.
Cellulose itself is insoluble in water because of its highly ordered structure and extensive intermolecular interactions. Its properties can be modified by chemical substitution of the hydroxyl groups at the C-2, C-3 and C-6 positions of the anhydroglucose units. In hypromellose, these hydroxyl groups are partially substituted with methoxy (MeO) and hydroxypropoxy (HPO) groups, producing a water-soluble cellulose ether with properties that depend on its molecular structure and substitution characteristics.
HPMC is not a single, molecularly uniform substance. Differences in molecular weight and molecular-weight distribution, degree of substitution, molar substitution, substituent distribution, raw-material origin and manufacturing conditions can influence its physicochemical and functional properties. Consequently, two HPMC batches or grades that comply with the same pharmacopoeial requirements may still behave differently in a pharmaceutical formulation.
Excipia characterizes these properties beyond routine Certificate of Analysis (CoA) testing to help understand HPMC variability, functionality and its impact on drug product performance.
Figure 1 Structural formula of hypromellose (HPMC). The substituent R represents either a -H, -CH3 or a -CH2CH(CH3)OH
Hypromellose Characterization Services
Our capabilities include detailed substituent-distribution analysis, molecular-weight distribution (MWD), degree and molar substitution, reactive components, degradation products and other composition- and functionality-related characteristics.
These investigations can support HPMC supplier and grade selection, batch comparison, formulation troubleshooting and the identification and control of relevant Functionality Related Characteristics (FRCs).
Applications of Hypromellose
Hypromellose has a broad range of applications in pharmaceutical, food and industrial products. In pharmaceuticals, HPMC is widely used in oral and topical drug products as a tablet binder, granulation aid, film-forming and coating polymer, capsule material, viscosity modifier, thickening agent and release-modifying polymer.
One of its most important pharmaceutical applications is the use of higher-viscosity HPMC grades in hydrophilic matrix tablets for modified or controlled drug release. Following contact with aqueous media, HPMC hydrates and forms a gel layer around the tablet. Drug release may subsequently be governed by a combination of drug diffusion through the hydrated polymer matrix and erosion of the HPMC gel layer. The relative importance of these mechanisms depends on the formulation, drug properties and characteristics of the HPMC used.
Outside pharmaceutical applications, hypromellose is also used in food, nutrition, ophthalmic, construction and other applications because of its film-forming, thickening, stabilizing and surface-active properties.
The pharmaceutical functionality of HPMC depends not only on its nominal grade and viscosity but also on characteristics such as molecular weight and molecular-weight distribution, degree and pattern of substitution, particle properties and material variability. These properties are discussed in more detail below.
Read more below about the production, composition and purity of HPMC, hypromellose variability and HPMC characterization.
Hypromellose production
For the production of hypromellose, purified cellulose pulp is first treated with concentrated sodium hydroxide solution. This treatment swells the cellulose and disrupts its ordered structure, increasing accessibility of the hydroxyl groups. Methyl chloride and propylene oxide are subsequently reacted with the alkali cellulose to introduce methyl and hydroxypropyl ether substituents onto the cellulose backbone.
Derivatization occurs through methylation and hydroxypropylation reactions (reactions 1 and 2). Hydroxypropyl substitution can generate additional hydroxyl groups that may undergo further reaction. Consequently, the molar substitution with hydroxypropyl groups is not theoretically limited to the three hydroxyl groups originally present on each anhydroglucose unit.
The substitution process can be influenced by parameters including temperature, reagent concentrations, the ratio of methyl chloride to propylene oxide, reaction time and the point at which the reagents are introduced. Mixing and the distribution of alkali within the cellulose are also important because the etherification reaction occurs under heterogeneous conditions.
Cell-OH + NaOH + CH3Cl → Cell-OCH3 + H2O + NaCl (1)
Cell-OH + CH3-HCCH2O → Cell-O-CH2-CHOH-CH3 (2)
After reaction, the material is washed to remove sodium chloride and residual process-related components. The resulting HPMC wet cake is dried and milled to obtain the required particle characteristics. Certain low-viscosity HPMC grades are subsequently subjected to controlled acid hydrolysis to reduce the average degree of polymerization.
Viscosity is commonly used as an indirect measure related to polymer chain length and is an important parameter, together with the degree of substitution, for defining commercial HPMC grades. Batches may also be blended before packaging to achieve the required viscosity specification and improve product consistency.
However, the same apparent viscosity can be obtained from HPMC materials with substantially different molecular-weight distributions (MWDs). For example, blending material with relatively high and low molecular weight may produce an average viscosity within the specification of a particular HPMC grade, while the resulting polymer population differs considerably from that of a more homogeneous batch having the same apparent viscosity without blending. Routine viscosity testing alone cannot reveal this difference.
Such differences in molecular-weight distribution may become relevant to HPMC hydration, gel formation, erosion and ultimately drug product performance. Measurement of the HPMC molecular-weight distribution therefore provides additional information beyond viscosity and can be used to compare grades, suppliers and batches and to investigate otherwise unexplained differences in formulation performance.
Why Pharmaceutical Hypromellose Can Vary
Hypromellose is manufactured from cellulose, a natural polymer commonly obtained from wood pulp or cotton linters. Variation in the cellulose starting material, including polymer chain length and composition, can contribute to differences in the resulting HPMC. Additional variability can arise during chemical modification. The conversion of cellulose into hypromellose is generally performed under heterogeneous reaction conditions, in which the cellulose starting material and resulting cellulose ether remain present as solid phases during important stages of the process. Uniform swelling, alkali distribution and mixing are therefore important. If the cellulose is not uniformly accessible to the etherification reagents, some regions can become more highly substituted than others. Heterogeneity may occur along an individual polymer chain, between different polymer chains and between domains or populations of polymer chains. The resulting substitution pattern can influence water interaction, hydration, solubility, gel formation and other functional properties of HPMC. Regions with relatively low substitution may, for example, show reduced solubility compared with more uniformly substituted material. Consequently, HPMC materials with similar average pharmacopoeial properties may still differ at the molecular level in ways that can become relevant to pharmaceutical performance.
Read also our Case Study: VARIABILITY OF EXCIPIENTS: Xylose in microcrystalline cellulose
Figure 2 Schematic illustration of different substituent distributions in Hypromellose (Richardson S., et al.)
Degree of Substitution, Molar Substitution and HPMC Substitution Pattern
Each anhydroglucose unit in cellulose contains three hydroxyl groups, located at the C-2, C-3 and C-6 positions. During HPMC manufacture, these positions may remain unsubstituted or may be substituted with methyl or hydroxypropyl groups. Because the three hydroxyl groups differ in accessibility and reactivity, substitution does not necessarily occur with equal probability at each position. At the monomer level, this results in a large number of possible substitution configurations. Further substitution of hydroxyl groups introduced through hydroxypropylation increases the structural complexity even further.
Two commonly used parameters describe the average extent of substitution:
Degree of substitution (DS) represents the average number of original cellulose hydroxyl groups substituted per anhydroglucose unit and therefore ranges from 0 to 3.
Molar substitution (MS) represents the average number of substituent molecules introduced per anhydroglucose unit. Because hydroxypropyl groups introduce new hydroxyl functionality that can undergo further substitution, MS is not theoretically limited to 3.
However, DS and MS are average values. They do not fully describe how methyl and hydroxypropyl groups are distributed between individual glucose units, along individual cellulose chains or between different polymer chains.
This distinction is important because molecular weight, degree of substitution and substituent distribution collectively influence the hydrophilic/hydrophobic character, hydration behaviour and functionality of HPMC.
Functionality Related Characteristics (FRCs) of Hypromellose
For pharmaceutical excipients such as hypromellose, compliance with a pharmacopoeial monograph does not necessarily mean that different batches, grades or suppliers will perform identically in a particular formulation. Properties that influence the functionality of an excipient in a drug product are commonly referred to as Functionality Related Characteristics (FRCs). FRCs are physical, chemical, or microbiological characteristics of an excipient. The characteristics considered relevant depend on the excipient’s intended function and the specific formulation in which it is used.
For HPMC, potentially relevant FRCs include apparent viscosity, molecular weight and molecular-weight distribution, degree and molar substitution, detailed substituent distribution, particle characteristics and moisture content. Other composition-related characteristics may also become relevant depending on the application.
This is particularly important for modified-release formulations, where hydration, swelling, gel formation, diffusion and erosion of the HPMC matrix can determine drug-release behaviour. HPMC materials that comply with the same pharmacopoeial requirements and have similar CoA values may nevertheless differ in molecular-weight distribution or substituent distribution and consequently may not perform identically in a particular formulation.
Excipia can characterize these differences beyond routine CoA testing. Detailed analysis of more than 27 differently substituted anhydroglucose monomers provides a fingerprint of HPMC substituent distribution, while SEC analysis provides the molecular-weight distribution beyond the single apparent viscosity value. These measurements can help identify FRCs associated with differences in HPMC functionality and drug product performance.
Understanding and controlling relevant HPMC FRCs can support supplier and grade selection, batch comparison, formulation development and troubleshooting, change control and the establishment of additional material specifications where routine pharmacopoeial testing alone does not sufficiently control drug product performance.
HPMC Batch Variability and Its Impact on Drug Release
The potential pharmaceutical impact of HPMC variability became evident during the development of a controlled-release matrix tablet. Two lots of the same HPMC grade from the same manufacturer were used in otherwise identical formulations. The Certificate of Analysis (CoA) values of the two HPMC lots were very similar, yet substantial differences in drug-release performance were observed.
Tablets prepared with HPMC Lot A showed considerably faster drug release than tablets prepared with Lot B.
Additional experiments using USP Apparatus III (Bio-Dis), performed together with the Avivia dissolution team, investigated the behaviour of both the drug and HPMC matrix during dissolution. In this particular formulation, HPMC erosion occurred relatively rapidly and drug release was found to be predominantly erosion-controlled, with only a limited contribution from diffusion through the hydrated polymer matrix.
This made the formulation particularly sensitive to HPMC characteristics that affected hydration, gel behaviour and erosion.
Further characterization identified a relationship between HPMC substitution pattern and the observed dissolution behaviour. By introducing additional in-house characterization and material specifications beyond the routine CoA, HPMC batches with suitable properties could subsequently be identified and selected.
The case demonstrates why pharmacopoeial compliance alone may not always be sufficient to ensure equivalent functional performance of HPMC in a specific formulation.
In practice, detailed HPMC characterization can help explain formulation-performance differences that are not explained by HPMC grade, viscosity specification or routine CoA data alone.
The potential pharmaceutical impact of HPMC variability became evident during the development of a controlled-release matrix tablet. Two lots of the same HPMC grade from the same manufacturer were used in otherwise identical formulations. The Certificate of Analysis (CoA) values of the two HPMC lots were very similar, yet substantial differences in drug-release performance were observed.
Tablets prepared with HPMC Lot A showed considerably faster drug release than tablets prepared with Lot B.
Additional experiments using USP Apparatus III (Bio-Dis), performed together with the Avivia dissolution team, investigated the behaviour of both the drug and HPMC matrix during dissolution. In this particular formulation, HPMC erosion occurred relatively rapidly and drug release was found to be predominantly erosion-controlled, with only a limited contribution from diffusion through the hydrated polymer matrix.
This made the formulation particularly sensitive to HPMC characteristics that affected hydration, gel behaviour and erosion.
Further characterization identified a relationship between HPMC substitution pattern and the observed dissolution behaviour. By introducing additional in-house characterization and material specifications beyond the routine CoA, HPMC batches with suitable properties could subsequently be identified and selected.
The case demonstrates why pharmacopoeial compliance alone may not always be sufficient to ensure equivalent functional performance of HPMC in a specific formulation.
In practice, detailed HPMC characterization can help explain formulation-performance differences that are not explained by HPMC grade, viscosity specification or routine CoA data alone.
Be in control of your product!
HPMC Composition, Purity and Process-Related Components
Pharmaceutical hypromellose is typically supplied as a white or off-white hygroscopic powder, granules or fibrous material and is considered physiologically harmless, tasteless, and odorless. HPMC can reversibly absorb moisture from the environment; consequently, its water content may vary depending on the grade, storage conditions, and relative humidity. HPMC typically has the following composition: hydroxypropyl methylcellulose, 85–99%; water, 1–10%; and sodium chloride, 0.5–5%. In addition to the HPMC polymer itself, low levels of process-related substances, residual inorganic components, and substances originating from the cellulose raw material may also be present.
During HPMC manufacture, side reactions involving propylene oxide, methyl chloride and alkaline processing conditions can potentially generate low-molecular-weight process-related compounds. Reported substances include formaldehyde, acetaldehyde, methanol and other volatile or reactive components. Most process-related substances are removed during washing and drying, but trace levels of certain compounds may remain.
Additionally, three specific residual impurities are described that may, in theory, be found in hypromellose: propylene oxide and two chloropropanols, 3-chloro-l,2-propanediol and 1,3-dichloro-2-propanol. These three substances are controlled by the manufacturer at acceptable safety levels, i.e. below 5 ppm.
Residual substances associated with the manufacturing chemistry may therefore be relevant when detailed characterization is required, particularly where an API is sensitive to reactive excipient components.
Cellulose-source components
In case cellulose from wood pulp is used as source, hypromellose still may contain traces of lignin and hemicelluloses. Lignin is a phenolic substance consisting of an irregular array of variously bonded hydroxy- and methoxy-substituted phenylpropane units. Hemicelluloses are mixtures of polysaccharides synthesized in wood almost entirely from glucose, mannose, galactose, xylose, arabinose, 4-O methylglucuronic acid, and galacturonic acid residues. Generally, hemicelluloses are of much lower molecular weight (MW) than cellulose and some are branched.
Acid-degraded HPMC
Low viscosity grades of HPMC are obtained by hydrolysis of hypromellose with acid to lower the average degree of polymerization and obtain the product with desired low viscosity. Douša et al. showed that typical acid-catalyzed cellulose related degradation products like furfural, 5-hydroxymethylfurfural (HMF) and 5-methoxymethylfurfural (5-MMF) can be found in these grades at levels up to 10 ppm.
Molecules with very small chain length resulting from the breakdown of cellulose are known as cellodextrins; in contrast to long-chain cellulose, cellodextrins are typically soluble in water and organic solvents and are likely to be removed during wash steps.
Hypromellose is known to be a stable substance; like many other polysaccharides, hypromellose will start to degrade rather than exhibit melting behavior. Specifically, hypromellose will brown at 190 – 200°C, char at 225 – 230°C, and burn out between 260°C and 300°C. However, hypromellose has very good thermal stability at lower temperatures. An untreated hypromellose product can usually withstand 100°C for several hours without degradation or loss of effectiveness.
Like all modified celluloses, hypromellose has virtually no toxic effects as large molecular weight molecules are not significantly absorbed from the gastrointestinal system. When administered to human subjects, HPMC showed only mild laxative or constipating effects in several cases, and almost the complete dose was recovered from feces.
Pharmacopoeial Specifications and the Limitations of the HPMC CoA
Pharmaceutical HPMC is available in numerous substitution types, viscosity grades and particle-size variants. Low molecular weight hypromellose is typically used as binder and film-formers in coatings, while high molecular grades are used to control the release of the active ingredients in matrix tablets. Commercial nomenclature differs between manufacturers such as Benecel (Ashland), Metolose (Shin-Etsu) and Methocel (Dow/Dupont). The information that is provided with commercially available HPMC on the certificate of analysis (COA) is defined by the monographs in various pharmacopoeias.
Most pharmacopeial monographs for hypromellose include tests and specifications for identification, appearance of solution, pH, apparent viscosity, chloride, heavy metals, loss on drying, and sulphated ash. A test for the degree of substitution is also included to differentiate among the various substitution types of hypromellose. The specifications for the average methoxy (MeO) and hydroxypropoxy (HPO) contents of the three hypromellose types commonly used in hydrophilic matrix tablets are presented in the table below.
Substituent distribution
The pharmacopoeial ranges for methoxy and hydroxypropoxy content within the three HPMC substitution types are relatively broad and show some overlap. Together with apparent viscosity, these average values are among the principal characteristics commonly available from routine CoA data.
However, average degree of substitution does not describe the distribution of substituents within the HPMC polymer population. Differences may occur at the monomer level, along individual cellulose chains and between different polymer chains. Consequently, HPMC materials with similar average methoxy and hydroxypropoxy contents can still differ in their detailed molecular structure.
Substituent distribution can influence the hydrophilic/hydrophobic character, hydration, gel formation, solubility and other functional properties of HPMC, and may therefore become relevant to pharmaceutical performance.
Excipia can characterize HPMC substitution in considerably greater detail than the average methoxy and hydroxypropoxy contents reported on a routine CoA. Following depolymerization of the HPMC, more than 27 differently substituted anhydroglucose monomers can be separated and quantified, providing a detailed fingerprint of the substituent distribution. This enables HPMC materials from different batches, grades or suppliers to be compared at a level of structural detail that is not captured by average degree of substitution alone.
Molecular Weight, Viscosity and Molecular-Weight Distribution
In addition to substitution type, pharmaceutical HPMC is further classified according to viscosity, with commercial nomenclature for viscosity grades varying between suppliers. Apparent viscosity is strongly influenced by HPMC polymer chain length and is therefore widely used to define commercial HPMC grades. However, viscosity is a bulk property and does not provide a complete description of the underlying molecular-weight distribution (MWD).
Two HPMC materials can have the same or very similar specified viscosity while having substantially different molecular-weight distributions. One material may contain a relatively narrow population of polymer chain lengths, whereas another may contain a broader distribution or a mixture of lower- and higher-molecular-weight polymer populations. The resulting apparent viscosity can nevertheless fall within the same grade specification.
This distinction can be particularly relevant when HPMC batches are blended to meet a viscosity target. A blend of relatively low- and high-viscosity material may give the required apparent viscosity, while its molecular-weight distribution differs considerably from that of an HPMC batch that intrinsically exhibits the same viscosity.
Excipia determines and compares the molecular-weight distribution (MWD) of HPMC using size-exclusion chromatography (SEC). Rather than relying solely on a single bulk viscosity result, the molecular-weight profile provides information on the distribution of polymer chain lengths and can reveal differences in the shape and breadth of the distribution or the presence of different polymer populations. This enables comparison of HPMC batches, grades and suppliers that may have similar specified viscosities but substantially different molecular-weight profiles, revealing differences that cannot be identified from the viscosity value or routine CoA data alone.
Where HPMC functionality depends on polymer hydration, gel formation, diffusion or erosion, differences in molecular-weight distribution may contribute to differences in drug product performance. MWD characterization can therefore support supplier and batch comparison, formulation troubleshooting, identification of relevant Functionality Related Characteristics (FRCs), and the definition of additional material specifications where viscosity alone does not provide sufficient control.
Hypromellose Characterization Services
Excipia provides detailed analytical and physicochemical characterization of pharmaceutical hypromellose (HPMC) to investigate differences between grades, suppliers and batches and to understand material characteristics that may influence drug product performance.
Routine pharmacopoeial and Certificate of Analysis testing provides important information on parameters such as apparent viscosity and average methoxy and hydroxypropoxy content. However, HPMC materials with comparable CoA results may still differ substantially in their underlying molecular structure. Excipia can characterize these differences beyond routine CoA testing and help identify Functionality Related Characteristics (FRCs) that are relevant to a particular formulation.
Detailed HPMC Substituent Distribution
Excipia can characterize HPMC substitution in considerably greater detail than the average methoxy and hydroxypropoxy contents or DS/MS values normally reported for the material. Following depolymerization of HPMC, more than 27 differently substituted anhydroglucose monomers can be separated and quantified, providing a detailed fingerprint of the substituent distribution.
These fingerprints can be used to compare HPMC materials and identify structural differences between batches, grades or suppliers that are not apparent from average substitution values alone and, where relevant, investigate whether these differences are associated with changes in pharmaceutical functionality.
Molecular-Weight Distribution (MWD)
Excipia determines and compares the molecular-weight distribution of HPMC by size-exclusion chromatography (SEC). MWD analysis provides information on the distribution of polymer chain lengths beyond the single apparent viscosity value and can reveal differences in the breadth or shape of the distribution and differences between polymer populations.
This is particularly useful when HPMC materials have similar specified viscosities but different molecular-weight profiles, including materials or batches that have been blended to achieve a viscosity specification.
Additional HPMC Characterization
- Degree of substitution (DS) and molar substitution (MS);
- Comparison of non-hydrolysed and deliberately hydrolysed HPMC grades;
- HPMC hydration, dissolution and erosion behaviour;
- Investigation of release mechanisms in HPMC-containing formulations;
- Reactive components, impurities and functional groups;
- Reducing components and reducing power;
- Low-molecular-weight degradation products and related substances;
- Composition-related differences between suppliers, grades and batches.
Combining detailed substituent-distribution analysis, molecular-weight characterization and other relevant measurements can provide a much more complete understanding of HPMC variability than routine CoA testing alone.
These investigations can support supplier and grade selection, batch comparison, formulation development and troubleshooting, investigation of unexpected dissolution or stability behaviour, change control, and identification and control of relevant HPMC Functionality Related Characteristics (FRCs). Where appropriate, the results can also support the establishment of additional material specifications beyond routine pharmacopoeial or CoA requirements.
When Can More Detailed HPMC Characterization Help?
Additional HPMC characterization may be useful when:
- changing HPMC supplier, manufacturing site, grade or batch;
- unexplained changes in dissolution or drug-release behaviour are observed;
- HPMC matrix erosion, hydration or gel formation differs between formulations;
- routine CoA results do not explain differences in product performance;
- an API shows unexpected degradation in an HPMC-containing formulation;
- relevant HPMC Functionality Related Characteristics need to be identified, understood or more tightly controlled;
- comparing HPMC used in a reference product with potential formulation materials.
Frequently Asked Questions About Pharmaceutical HPMC
Can two pharmaceutical HPMC batches with the same viscosity perform differently?
Yes. Apparent viscosity is a bulk property and does not fully describe the molecular-weight distribution of HPMC. Two batches can have similar specified viscosities while differing in the distribution of polymer chain lengths. Differences in molecular-weight distribution, substitution pattern and other material characteristics may influence hydration, gel formation, erosion and drug-release behaviour in a particular formulation.
What is the difference between HPMC viscosity and molecular-weight distribution?
HPMC viscosity is a bulk measurement strongly influenced by polymer chain length, whereas molecular-weight distribution (MWD) describes the distribution of different polymer chain lengths within the material. HPMC materials with similar apparent viscosities can therefore have different molecular-weight profiles. Excipia uses size-exclusion chromatography (SEC) to compare HPMC molecular-weight distributions.
What is HPMC substituent distribution?
HPMC substituent distribution describes how methoxy and hydroxypropoxy groups are distributed within the HPMC polymer population. Average degree of substitution (DS) and molar substitution (MS) describe the overall extent of substitution but do not fully describe differences between individual anhydroglucose units or polymer populations. Excipia can separate and quantify more than 27 differently substituted anhydroglucose monomers to obtain a detailed HPMC substitution fingerprint.
What are Functionality Related Characteristics (FRCs) of HPMC?
Functionality Related Characteristics are material characteristics that can influence the functionality of an excipient in a particular pharmaceutical formulation. Potentially relevant HPMC FRCs include viscosity, molecular weight and molecular-weight distribution, degree and pattern of substitution, particle characteristics and moisture content. Which characteristics are relevant depends on the intended function of HPMC and the formulation.
Why can pharmacopoeial HPMC compliance be insufficient to explain drug product performance?
Pharmacopoeial specifications provide important controls for HPMC quality, but they do not describe every structural or functional characteristic that may be relevant to a particular formulation. HPMC batches that comply with the same monograph and have similar CoA values can still differ in molecular-weight distribution, detailed substituent distribution or other characteristics. Additional characterization can therefore be useful when routine CoA data do not explain differences in dissolution, stability or formulation performance.
How can HPMC variability be investigated when dissolution changes unexpectedly?
A useful investigation combines drug product performance testing with characterization of potentially relevant HPMC properties. Depending on the formulation, this may include molecular-weight distribution, detailed substituent distribution, DS/MS, hydration, dissolution and erosion behaviour, particle characteristics and reactive or degradation-related components. Comparing these results between well-performing and poorly performing batches can help identify material characteristics associated with the observed change.
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Discover our unique services such as quantitative excipient analysis, identification, selection or specific formulation development support. Don’t forget to check out our case studies.
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Menno Wiltink
Founder of Excipia.
