N,N-DIETHYL-M-TOLUAMIDE（DEET） Pharma Grade API is supplied as a clear, low-viscosity liquid at 25 °C, with a density of approximately 0.996 g/cm³ and a boiling range of 288–292 °C at atmospheric pressure. The material is designated for formulation screening in tablet, capsule, granule, and injectable dosage forms where the active is either adsorbed onto a solid carrier, incorporated as a liquid binder, or dissolved in a non-aqueous vehicle. The grade code DEET-Ph on the certificate of analysis identifies the pharma-grade lot; this code is an in-house designation and should not be interpreted as a harmonized pharmacopeial monograph, because no oral or injectable DEET monograph has been published in USP, Ph. Eur., or JP at the date of this document. Release specifications are derived from ICH Q3C, ICH Q3D, and current compendial general chapters. The principal difference from technical-grade DEET is the level of specified impurities and the addition of microbial, elemental impurity, residual solvent, and, for injectable lots, bacterial endotoxin controls.

Specification Profile and Compendial Alignment

The release profile is defined by gas chromatographic assay, related substances, water content, residue on ignition, residual solvents, elemental impurities, and microbiological quality. Because the material is liquid at ambient temperature, batch-to-batch variation in viscosity and density can alter pump calibration and spray uniformity. Each pharma-grade lot is therefore released with a certificate of analysis that includes density, refractive index, water content, assay, and related substances. The specification table below reflects the typical release limits applied to DEET-Ph lots for oral and injectable development.

For comparison, technical-grade DEET used in topical repellents is commonly released at ≥95% m-isomer content, with less stringent control of colour, odour, water, and residue on ignition. The pharma-grade material additionally restricts residual solvents to ICH Q3C limits and imposes a low bioburden specification. These differences become critical when DEET is incorporated into oral solid forms or sterile injectables, because compendial excipient compatibility and endotoxin load cannot be inherited from repellent-grade supply chains. The following table summarises the grade distinction.

What Limits the Use of DEET in Solid Oral Dosage Forms?

At ambient temperature, DEET remains a liquid, which prevents direct compression unless the liquid is pre-adsorbed or solidified by co-processing. The viscosity of the liquid is approximately 13.3 mPa·s at 25 °C, low enough for spraying onto carriers but high enough to cause overwetting and granule collapse if addition is not metered. In high-shear wet granulation, DEET can act as a binder, and its metered addition should be controlled through a peristaltic or screw pump linked to impeller torque. Granulation endpoint is assessed by sieve retention on 150 µm and 710 µm screens and by USP <1174> powder flow. Because DEET is a solvent for some polymers, wetted components in a twin-screw extruder or capsule machine should be limited to PTFE, polypropylene, or 316L stainless steel. Published data for DEET-specific granulation endpoints are limited; therefore, a design-of-experiments matrix covering liquid-to-carrier ratio, impeller speed, and wet massing time is required for each formulation.

For solid-dosage development, the liquid is typically combined with porous carriers such as magnesium aluminometasilicate, fumed silica, or microcrystalline cellulose. The carrier’s oil adsorption capacity, determined by a spatula rub-out method or by nitrogen adsorption porosimetry, must be measured before setting the DEET loading. The selected loading is usually kept below the measured adsorption capacity to preserve acceptable mass flow and compaction behaviour. The resulting adsorbed powder is blended with disintegrant and glidant, but magnesium stearate addition should be minimised because excessive hydrophobicity can delay dissolution, which is monitored by USP <711>. Compared with icaridin and ethyl butylacetylaminopropionate, DEET has a molecular weight of 191.27 g/mol and higher solvent strength; this must be considered when selecting shell materials, filters, and tubing.

Process Rheology and Granulation Endpoint Control

Temperature dependence of DEET viscosity introduces a processing window. At 20 °C to 30 °C, viscosity changes are modest, but cooling below 15 °C may increase line pressure and reduce spray uniformity. In continuous twin-screw granulation, DEET is injected through a liquid feed port downstream of the powder feed. The liquid-to-solid ratio, screw configuration, and barrel temperature profile are controlled to prevent phase separation of the liquid from the carrier. A co-rotating twin-screw extruder with L/D ratio 25–40 is often used for this purpose; however, published data for DEET in this configuration are limited, so the specific energy input and residence time distribution must be measured on the actual line. If the melt pressure exceeds the limit of the die plate, the granule can sinter and block the discharge; barrel venting or reduced fill level is then introduced. Near-infrared probe monitoring at the discharge can detect free liquid and trigger a feed-rate correction.

Torque rheometry data on the granulation mass provide a more reproducible endpoint than visual inspection. The torque curve may show a steep rise after the capillary state is reached, and the resulting granules can fail disintegration testing. A corrective action is to reduce liquid addition rate or increase impeller speed; however, if the formulation contains moisture-sensitive disintegrants, the adsorbed DEET carrier should be dried to water content ≤ 0.5% before blending. Loss on drying by USP <731> is used to confirm that residual moisture is not elevated. For tablet compression, DEET-loaded granules are compressed on a rotary tablet press with precompression and main compression force set to produce tablets with hardness 50–100 N and friability ≤ 1.0%. Ejection force should be monitored because DEET-adsorbed granules may exhibit higher wall friction if carrier loading approaches saturation.

In hard-shell capsule operations, two approaches are used: dry powder capsules containing DEET adsorbed onto a carrier, and liquid-filled hard-shell capsules sealed at the cap-body interface. For dry powder capsules, the granule blend moisture should be kept below 3% w/w to avoid shell cracking, and the capsule fill weight is controlled using tamping pins or dosator settings that must be qualified for the DEET-loaded blend. Encapsulation on an automatic capsule machine requires fill weight control within ±5% of target. Powder flow can be improved by addition of colloidal silicon dioxide at 0.5–1.5% w/w. For liquid-filled hard-shell capsules, the fill formulation must have a viscosity suitable for precision dosing at 25–35 °C; if viscosity is too low, micro-leakage at the cap-body gap can occur before sealing. The shell material and banding solution must resist plasticization by DEET; gelatin and HPMC compatibility screening is performed over 3–6 months at 40 °C/75% RH according to ICH Q1A(R2) accelerated conditions.

For oral liquid development, the low aqueous solubility of DEET requires a solvent system such as PEG 400, propylene glycol, or a cyclodextrin-based complex. Phase solubility studies should be performed to identify the minimum co-solvent content that maintains a stable single phase at 2–8 °C and 25 °C; physical stability under refrigeration is often the limiting factor. Flavour masking is necessary because the drug substance has a bitter, solvent-like note; this is addressed through sweeteners, flavour oils, or taste-masking excipients rather than by heating, which may accelerate oxidation. The oral liquid container should be glass or PET with a child-resistant closure and an oral dosing syringe; compatibility of the wetted components with DEET must be evaluated because DEET may extract plasticisers from some elastomers.

When Sterile Injectable Formulation Requires Low Endotoxin DEET

Because DEET is poorly water-soluble, a simple aqueous solution for injection is not feasible without a cosolvent or surfactant system. Typical screening vehicles include PEG 400, propylene glycol, ethanol, and water for injection in ratios established by phase-solubility studies. The API lot used for injectable development must meet the endotoxin limit derived from USP <85>; if maximum clinical dose is not fixed, a conservative release limit of 0.5 EU/mg is commonly used for early parenteral formulations. Terminal moist-heat sterilization at 121 °C for 15 min should be supported by forced-degradation data because DEET can undergo hydrolysis or oxidation under stressed conditions. If such data are insufficient, sterilising filtration through 0.22 µm PVDF or PTFE membranes is preferred, provided the membrane filter validation demonstrates no plasticization or leachable formation. Filter validation should include bubble point, pressure decay, and bacterial challenge testing per ASTM F838-20; extractables assessment follows USP <665> and USP <1663> for plastic components.

Container-closure systems should use Type I borosilicate glass or cyclo-olefin polymer; natural rubber, polychloroprene, and silicone tubing may extract DEET or swell. The formulation should also be tested for haemolytic potential and injection-site pain, because high ethanol or propylene glycol content may require dilution prior to injection. A prefilter of 0.45 µm may be used upstream of the sterilising membrane if the formulation is viscous or contains particulate matter. The same pharma-grade liquid can be used for oral and injectable development, but injectable lots are released with stricter endotoxin and particulate controls. Oral lots may be released only against USP <61>/<62> and residual solvents; injectable lots must additionally meet sterility, bacterial endotoxins, and particulate matter tests per USP <788>. Use of DEET in injectable forms remains outside approved labelling; any use must be governed by an approved investigational protocol.

Analytical release of pharma-grade DEET relies on gas chromatography with flame ionisation detection for assay and related substances; residual solvents are quantified by headspace GC-MS following USP <467> procedure A. Forced-degradation studies should include acidic, alkaline, oxidative, thermal, and photolytic stress per ICH Q1A(R2); the amide bond may hydrolyse to m-toluic acid and diethylamine under extreme pH, so pH stress testing should bracket 1.0–13.0 at elevated temperature. If hydrolysis is observed, a formulation pH is selected that minimises amide cleavage while maintaining acceptable solubility. Quantitation of degradation products uses peak area normalisation with response factors verified against authentic reference standards. Published data for DEET-specific forced degradation in parenteral vehicles are limited; therefore, degradation product identification must be performed on each formulation rather than assumed from the drug substance alone.

Store in tightly closed, light-resistant containers under nitrogen headspace at 15–25 °C. Protect from heat, open flame, and direct sunlight. Avoid contact with natural rubber, flexible PVC, polycarbonate, and uncured epoxy coatings; use glass, 316L stainless steel, or PTFE-lined equipment for transfer and storage.