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Hypromellose phthalate

Table of contents

Other Names

2-Hydroxypropyl methyl cellulose phthalateCellulose methyl 2-hydroxypropyl ether hydrogen phthalate esterHPMC-PHPMCPHydroxypropyl methycellulose phthalateHydroxypropyl methyl cellulose phthalateHydroxypropyl methylcellulose phthalate

Synopsis

Hypromellose Phthalate (HPMCP): A Comprehensive Reference

1. Identity, Chemical Nomenclature, and Natural Source

1.1 Names and Identifiers

Hypromellose phthalate (hydroxypropyl methylcellulose phthalate, or HPMCP) is a phthalic acid ester of hydroxypropyl methylcellulose. The compound is known under several synonyms, including hydroxypropyl methyl cellulose phthalate, HPMC phthalate, HPMC-P, and HP-55/HP-50 (referring to commercial grades). Its CAS registry number is 9050-31-1. The INN/USAN designation "hypromellose phthalate" is used in all major pharmacopeias.

1.2 Chemical Structure and Composition

Hypromellose phthalate is a monophthalic acid ester of hydroxypropyl methylcellulose. It contains methoxy (–OCH3), hydroxypropoxy (–OCH2CHOHCH3), and phthalyl (o-carboxybenzoyl; C8H5O3) groups. Per USP/NF specifications, it contains not less than 21.0% and not more than 35.0% of phthalyl groups, calculated on the anhydrous basis.

HPMCP is a cellulose derivative having methoxy groups (–OCH3), hydroxypropoxy groups (–OC3H6OH), and carboxybenzoyl groups (–COC6H4COOH), and is produced by chemically modifying cellulose.

1.3 Natural Source and Botanical Origin

HPMCP is derived from cellulose, which is a natural polymer that forms the structural component of plant cell walls. Cellulose is a biodegradable polymer of natural origin composed of repeated units of glucose. The primary industrial source of cellulose for pharmaceutical-grade HPMCP is wood pulp. In cases where cellulose from wood pulp is used as source, hypromellose may contain traces of lignin and hemicelluloses.

Importantly, HPMCP is a semi-synthetic material: it begins with plant-derived cellulose but undergoes extensive chemical transformation. Its intermediate, hypromellose (HPMC), is produced by treating alkali cellulose with methylating and hydroxypropylating agents. HPMCP is then produced by reacting HPMC with phthalic anhydride, which serves as the esterifying agent, in the presence of a catalyst. HPMCP is therefore not extracted directly from any plant; it has no traditional botanical use in its current form.

1.4 Physical Appearance

Hypromellose phthalate is a colorless, odorless white powder. It is odorless or possesses a slightly acidic odor and has a barely detectable taste. Commercially it may also appear as white to off-white free-flowing flakes or granules.

1.5 Pharmacopeial Status and Commercial Grades

HPMCP has been admitted into the NF (United States National Formulary), EP (European Pharmacopoeia), and JP (Japanese Pharmacopoeia).

It dissolves at pH 5–5.5, and this property can be controlled by varying the phthalyl content. Two grades of different pH solubility, HP-55 and HP-50, are available. The appropriate grade of HPMCP for a particular purpose should be selected in accordance with its properties and formulations. Specifically, HP50 and HP55 dissolve at pH 5.0 and 5.5, respectively. A third grade, HP-55S, is distinguished from HP-55 by differences in molecular weight and phthalyl content.

2. Historical and Industrial Development

2.1 Introduction to the Market

Hypromellose phthalate was introduced in 1971 as a cellulose derivative for enteric coating. Since the introduction of HPMCP (hypromellose phthalate USP/NF, JP, EP) in 1971, it has proved its value in enteric coating using organic solvent.

HPMCP has no traditional or pre-modern history of use. It is an entirely synthetic pharmaceutical excipient developed in the twentieth century for the oral drug delivery industry. Unlike botanical or mineral ingredients with centuries-old therapeutic traditions, HPMCP was designed specifically to solve a technical problem in pharmaceutical formulation — namely, how to protect drugs from destruction by gastric acid and to target their release to the upper small intestine.

2.2 Evolving Applications Since 1971

Since its introduction into the market in 1971 as an enteric coating, HPMCP has been demonstrated to be effective by many researchers, and it is widely used by the pharmaceutical industry. Over subsequent decades its applications expanded beyond simple tablet coatings to include sustained-release systems, nanoparticle platforms, amorphous solid dispersions, and antiviral microbicide research (see Sections 5 and 6 below).

3. Key Chemical Constituents and Manufacturing

3.1 Chemical Synthesis

HPMCP is produced by esterification of hypromellose with phthalic acid and is available in a range of different grades, depending on the degree of phthalation and the molecular weight of the polymer. More precisely, HPMC is reacted with phthalic anhydride in the presence of a catalyst to obtain the reaction product. In this step, a reaction product solution of HPMCP is obtained by esterifying hypromellose with a carboxybenzoylating agent in the presence of an aliphatic carboxylic acid.

3.2 Substitution Parameters

The degree of substitution (DS) of the methoxy groups of HPMCP is preferably from 1.10 to 2.20. The molar substitution (MS) of the hydroxypropoxy groups is preferably from 0.10 to 1.00. The DS of the carboxybenzoyl groups is preferably from 0.10 to 2.50, and more preferably from 0.10 to 1.00. These three classes of functional groups together determine pH solubility, film-forming properties, and biological behavior.

3.3 Physicochemical Stability

Hypromellose phthalate is chemically and physically stable at ambient temperature for at least 3–4 years and for 2–3 months at 40°C and 75% relative humidity. It is stable on exposure to UV light for up to 3 months at 25°C and 70% relative humidity. After 10 days at 60°C and 100% relative humidity, 8–9% of carboxybenzoyl groups were hydrolyzed, indicating that extreme heat and moisture can degrade the phthalyl ester linkages.

4. Mechanism of Action in Drug Delivery

4.1 pH-Dependent Enteric Behavior

HPMCP is a water-soluble, anionic polymer that is commonly used as an enteric coating material due to its excellent film-forming properties, stability, and resistance to gastric fluids. Its fundamental mechanism rests on the ionization state of the pendant carboxylic acid groups in the phthalyl moiety.

At low pH in the stomach, the polymer is impermeable and insoluble, but in the higher pH environment present in the small intestine (e.g., >5.5), the polymer dissolves and exposes the core tablet for rapid- or slow-release of the actives. Hypromellose phthalate is insoluble in gastric fluid but will swell and dissolve rapidly in the upper intestine.

An enteric coating agent is used to protect drugs from degradation by gastric acid or to prevent them from causing side effects in the stomach. This dual protective and delivery function explains HPMCP's longstanding utility across a wide spectrum of acid-labile active pharmaceutical ingredients (APIs).

4.2 Supersaturation Maintenance in Amorphous Solid Dispersions

The ability of polymeric excipients to maintain the drug in a supersaturated state in the gastrointestinal tract upon dissolution into GI fluids makes them more desirable than other solubilizing strategies. HPMCP functions as both a crystallization inhibitor and a solubilizing matrix in amorphous solid dispersions (ASDs). A variety of polymers have been reported in the literature as enabling and stabilizing excipients for amorphous solid dispersions including, but not limited to, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), and others.

4.3 Polyanionic Antiviral Mechanism

In its dissolved, ionized state, HPMCP functions as a polyanionic macromolecule — that is, a polymer carrying multiple negative charges along its backbone. Polyanionic macromolecules including carboxylate-terminated polymers (polycarboxylates) are capable of inhibiting sexually transmitted viruses such as human immunodeficiency virus (HIV) and herpes simplex virus (HSV).

The mechanism of anti-CMV and anti-HSV activity of polyanionic compounds can be attributed to the inhibition of virion attachment to the cells, probably due to an interaction of these polyanionic compounds with the positively charged domains of the viral envelope glycoproteins. Because HPMCP carries carboxylate anions (from the phthalyl groups) in neutral to alkaline pH, it is proposed to electrostatically interfere with viral glycoprotein binding to host cell surface heparan sulfate proteoglycans.

A key property of HPMCP is its ability to remain dissociated in solution and molecularly dispersed even after exposure to a low-pH environment, whereas the exposure of cellulose acetate phthalate (CAP) to a low-pH environment for even a brief period of time dramatically lowered its antiviral effectiveness. This difference in aqueous stability between grades gives HPMCP a potential advantage over CAP for topical microbicide formulation.

5. Scientific Evidence by Area of Application

5.1 Enteric Coating of Oral Dosage Forms

Evidence Type and Strength

Established pharmaceutical application with decades of regulatory acceptance.

Hypromellose phthalate is widely used in oral pharmaceutical formulations as an enteric coating material for tablets or granules. Generally, concentrations of 5–10% of hypromellose phthalate are employed with the material being dissolved in either a dichloromethane:ethanol (50:50) or an ethanol:water (80:20) solvent mixture.

Hypromellose phthalate can normally be applied to tablets and granules without the addition of a plasticizer or other film formers, using established coating techniques. However, the addition of a small amount of plasticizer or water can avoid film cracking problems; many commonly used plasticizers, such as diacetin, triacetin, diethyl and dibutyl phthalate, castor oil, acetyl monoglyceride, and polyethylene glycols, are compatible with hypromellose phthalate.

Enteric coated preparations are among the most important solid dosage forms and are widely used for administering acid-labile drugs and protecting the gastric mucosa. The evidence base for HPMCP's enteric function is primarily derived from decades of formulation science, dissolution testing, and regulatory experience rather than clinical trials designed to test HPMCP itself — which reflects the standard for excipients rather than active therapeutic agents.

5.2 Sustained-Release and Modified-Release Preparations

Evidence Type and Strength

Established formulation technology; preclinical and in vitro data predominate; some clinical products contain HPMCP.

HPMCP is also used in sustained-release preparations, in binders, and as microcapsule bases. The family of HPMC-based excipients, including HPMCP and HPMCAS, plays an irreplaceable role in the formulation of traditional oral dosage forms with controlled release.

A notable real-world clinical example is pancreatic enzyme replacement therapy for cystic fibrosis. Creon (pancrelipase) capsules — which have been evaluated in head-to-head clinical trials — contain hypromellose phthalate as part of the enteric-coated microsphere shell, alongside polyethylene glycol and triethyl citrate.

5.3 Amorphous Solid Dispersions (ASD) for Bioavailability Enhancement

Evidence Type and Strength

Mostly preclinical and in vitro; some animal pharmacokinetic data; few published human clinical trials specifically testing HPMCP-based ASDs as the variable.

Usually used excipients for forming ASDs are cellulose derivatives such as hydroxypropyl methylcellulose (HPMC), hypromellose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), and others. These systems comprise an amorphous active pharmaceutical ingredient stabilized by a polymer matrix to provide enhanced stability.

Hot melt extrusion (HME) is one established method for producing HPMCP-containing ASDs. HPMCP is widely used for a solid dispersion obtained by hot melt extrusion or spray drying, wherein the HPMCP is used together with a water-insoluble drug. In a study evaluating ternary systems, products exhibited improved solubility and maintenance of supersaturated concentration when compared to crystalline griseofulvin, physical mixture, or extruded products resulting from binary formulation with HP alone.

Animal (dog model) data demonstrated that both of the melt-extruded solid dispersions containing 20% and 30% drug loading demonstrated a significantly higher bioavailability compared with the control formulation containing 20% crystalline drug triturated with poloxamer. These findings are preclinical; their translation to human bioavailability enhancement has not been directly tested in published randomized clinical trials where HPMCP itself was the independently evaluated variable.

5.4 Colonic and Lower Gastrointestinal Drug Delivery

Evidence Type and Strength

Preclinical and in vitro; no human clinical trials identified specifically for HPMCP-mediated colon targeting.

HPMCP (hydroxypropyl methylcellulose phthalate) has been investigated as a crosslinking agent for chitosan nanoparticles as a colon drug delivery system for ulcerative colitis (UC). Ulcerative colitis with continuous and extensive inflammation is limited to the colon mucosa. Conventional therapies are associated with several limitations including systemic side effects, drug degradation and inactivation, and limited drug uptake. These restrictions necessitate drug delivery to the colon so that the drug passes through the stomach unchanged and has selective access to the colon.

pH was a determining factor for releasing drug cargo from CS/HPMCP nanoparticles, as a higher cargo-releasing rate was observed in a less acidic environment. This behavior makes HPMCP-chitosan nanoparticle systems inherently suited to intestinal-pH drug release. This research is at the preclinical stage.

5.5 Oral Vaccine and Antigen Delivery

Evidence Type and Strength

Preclinical and in vitro only; no human clinical trials identified.

HPMCP has attracted research interest as a carrier for oral antigen delivery owing to its pH-sensitive dissolution properties and mucoadhesive character. The goal of one research program was to design an optimal ileum-specific protein delivery vehicle by attuning the pH-sensitive and mucoadhesive properties of HPMCP with cysteine molecules.

For hepatitis B surface antigen (HBsAg) delivery, HBsAg-loaded trimethyl chitosan (TMC)/HPMCP nanoparticles with a particle size of 158 nm showed loading capacity and loading efficiency of 76.75% and 86.29%, respectively, at 300 μg/mL concentration of the antigen, exhibiting improved acid stability and better protection of entrapped HBsAg from gastric destruction in vitro. Based on these findings, it was suggested that TMC/HPMCP nanoparticles have potential to be applied in the oral delivery of HBsAg vaccine. All findings in this area are preclinical.

5.6 Antiviral Activity: HIV and Herpes Simplex Virus

Evidence Type and Strength

In vitro (cell culture) evidence exists for HPMCP-55S specifically; no human clinical trials identified for HPMCP as a microbicide. Research interest was early-stage and largely superseded by other approaches.

Polyanionic macromolecules including carboxylate-terminated polymers are capable of inhibiting sexually transmitted viruses such as HIV and HSV. Cellulose acetate phthalate, a closely related pharmaceutically acceptable pH-sensitive polycarboxylate polymer, showed promising prophylactic activity against HIV and HSV, but instability of CAP in an aqueous environment prevented its clinical development.

A 2020 peer-reviewed study published in Antimicrobial Agents and Chemotherapy (PMID 33078609) evaluated specific grades of HPMCP as antiviral agents. The study was the first to demonstrate that PVAP, HPMCP-55S, and Eudragit S100 have activity and selectivity against HSV-1 and HSV-2. Further, polycarboxylates were reported to be easily transformed into nanoparticles, and in the nanoparticulate form, they show similar or enhanced activity against HSV. Using PVAP nanoparticles as a model, the study demonstrated using in vitro HSV therapy studies that polycarboxylate nanoparticles are capable of synergizing with antiviral drugs such as acyclovir, tenofovir, and tenofovir disoproxil fumarate.

Critically, it is possible that only HPMCP-55S has the right balance of molecular weight and phthalyl content to exhibit antiviral activity, suggesting that not all grades of HPMCP are equally active. All antiviral findings to date remain at the in vitro level. Pharmaceutically acceptable carboxylic acid-terminated polymers and their nanoparticles have the potential to be developed into topical formulations for the prevention and treatment of HSV infection, but this potential has not yet been realized in human clinical trials.

6. Body Systems and Health Areas Associated with HPMCP

  • Gastrointestinal system: The primary domain of HPMCP. It is used to protect drugs from gastric acid, target drug release to the duodenum and jejunum, and deliver agents to the colon.
  • Immunological system (via oral vaccine delivery): Preclinical research explores HPMCP nanoparticles as oral antigen carriers targeting Peyer's patches and mucosal immune induction. Orally delivered proteins or antigens are taken up by epithelial microfold cells (M cells) in Peyer's patches, especially abundant in the ileum of the small intestine.
  • Infectious disease / virology (topical/mucosally): HPMCP-55S's polyanionic antiviral activity, demonstrated in vitro against HSV-1, HSV-2, and HIV, suggests a potential future role in sexually transmitted infection prevention formulations.
  • Pharmacokinetic enhancement (across therapeutic categories): By enabling amorphous solid dispersions of BCS Class II and IV drugs, HPMCP indirectly affects bioavailability across a broad range of therapeutic areas including antifungals, immunosuppressants, antiretrovirals, and oncology agents.

7. Dosage Forms and Concentration Ranges

HPMCP is used exclusively as a functional excipient, not as a standalone therapeutic agent. All concentrations and quantities described below are derived directly from published formulation literature.

  • Tablet and granule enteric coatings (traditional organic solvent process): Concentrations of 5–10% of hypromellose phthalate are employed, with the material dissolved in either a dichloromethane:ethanol (50:50) or an ethanol:water (80:20) solvent mixture.
  • Amorphous solid dispersions (spray drying): In one published formulation, the drug and hypromellose phthalate were dissolved at a 1:2 weight ratio in a dichloromethane and methanol mixture (1:1, v/v), and then the formulation was prepared via spray drying.
  • Nanoparticles for antigen delivery: In one nanoparticle system, a concentration of 300 μg/mL of HBsAg antigen was incorporated into TMC/HPMCP nanoparticles of approximately 158 nm particle size.
  • Chitosan crosslinked nanoparticles for colon delivery: CS/HPMCP nanoparticles had an average size of 235.5 ± 42 nm, with loading capacity and entrapment efficiency of 79.78% and 75.79%, respectively, for the model cargo.
  • Antiviral microbicide research (in vitro): All polyanions used in cell-based antiviral studies were suspended in 50 mM sodium citrate buffer (pH 7.0) at concentrations ranging from 2 to 5%.

8. Safety Considerations

8.1 General Toxicological Profile

Chronic and acute animal feeding studies on several different species have shown no evidence of teratogenicity or toxicity associated with hypromellose phthalate. Hypromellose phthalate is generally regarded as a nonirritant and nontoxic material.

The EMA's dedicated Guideline on the use of phthalates as excipients in human medicinal products reviewed preclinical toxicology for HPMCP specifically. There is very limited published scientific literature available concerning the toxicity of HPMCP in general and reproductive and developmental toxicity of HPMCP in particular. In rats administered HPMCP orally via gavage, histopathology and organ weight evaluations revealed no effect on the reproductive organs following repeat-dosing of up to 6 g/kg body weight/day HPMCP for 6 months. In view of the above data, no permitted daily exposure (PDE) is deemed to be required for HPMCP.

Animal toxicology studies reviewed by FDA for NDA 22-210 included: 30-day and 6-month oral toxicity studies with HPMCP in rats; a 27-week oral toxicity study with HPMCP in dogs; and a reproductive toxicity study with HPMCP in mice and rats.

8.2 Distinction from Industrially Hazardous Phthalates

A critical regulatory and toxicological distinction exists between HPMCP and the small-molecule diester phthalates (such as DEHP and DBP) that are known endocrine-disrupting substances.

Several different phthalates are currently used as excipients in approved pharmaceutical formulations: diethyl phthalate (DEP), dibutyl phthalate (DBP), dimethyl phthalate (DMP), dioctyl phthalate (DOP), hypromellose phthalate (HMP), cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), and polyethylene terephthalate (PET). These are chemically very different compound classes despite sharing the word "phthalate."

Phthalate polymers with no known toxicity — hypromellose phthalate (HMP), cellulose acetate phthalate (CAP), and polyvinyl acetate phthalate (PVAP) — were included in 75 prescription drug products reviewed in a 2012 population exposure survey published in Environmental Health Perspectives.

Some ortho-phthalates, including di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DBP), have been identified as reproductive and developmental toxicants in laboratory animals. These adverse effects are associated with free small-molecule phthalate diesters, not with polymeric phthalate esters such as HPMCP, which have a very different toxicokinetic profile.

8.3 Regulatory Status and Phthalate Exposure Considerations

There has been some concern over the use of phthalates in medications, total exposure to phthalates, and possible toxicity, although specific research on polymeric phthalates is lacking. Phthalates are included in FDA's list of inactive ingredients for FDA-approved drugs. Phthalates are known to be excreted in the urine, although data on accumulation are not known.

Data currently available for the phthalates CAP, HPMCP, and PVAP do not indicate that their presence in human medicinal products constitutes a potential risk for human safety. The EMA guideline nonetheless acknowledges that the evidence base for HPMCP-specific safety is limited, and calls for manufacturers to continue monitoring and reporting toxicological findings.

8.4 Biocompatibility and Cell Studies

Hypromellose phthalate is used to create delayed-release capsules that resist stomach acid. Biocompatibility testing on these modified capsules has shown they are non-toxic and compatible with human cells, with live cell counts actually increasing in the presence of the polymer during laboratory testing.

8.5 Physical and Chemical Stability Considerations

Hypromellose phthalate is chemically and physically stable at ambient temperature for at least 3–4 years and for 2–3 months at 40°C and 75% relative humidity. The phthalyl ester bonds are susceptible to hydrolysis under conditions of high heat and moisture, which is a relevant consideration for storage and formulation. Drums stored in a cool, dry place should be brought to room temperature before opening to prevent condensation of moisture on inside surfaces.

8.6 Known Drug–Excipient Interactions

No clinically relevant pharmacokinetic drug-drug interactions attributable to HPMCP itself have been established in the literature. As an enteric coat, HPMCP affects the timing but not the chemical identity of drug release. It is chemically unreactive toward most APIs under normal storage conditions. The selection of plasticizers compatible with HPMCP (diacetin, triacetin, castor oil, PEGs) is a manufacturing consideration rather than a clinical safety issue. HPMCP is anionic and could theoretically interact electrostatically with strongly cationic active pharmaceutical ingredients, but this is a formulation design variable routinely managed in the pharmaceutical development process.

Summary of Evidence Quality

HPMCP occupies an unusual position in the pharmacological literature: it has a thoroughly established and decades-long record of safe pharmaceutical use as an excipient, but its potential as an active biological or therapeutic agent — notably in antiviral microbicides and mucosal vaccine delivery — is at an early, primarily in vitro stage of investigation. No published randomized controlled clinical trials (RCTs) have tested HPMCP as an independent therapeutic variable in humans. Its safety profile is well characterized in animals at high doses, and regulatory authorities in both the United States (FDA/NF) and Europe (EMA/EP) have explicitly concluded that HPMCP in pharmaceutical products does not constitute a known safety risk at the concentrations used in approved products.

References

Health Conditions

Health conditions that Hypromellose phthalate may help support.

  • No conditions available.

Body Systems

Body systems that Hypromellose phthalate may help support.

  • No body systems available.
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