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Topical cream formulation

Topical cream formulation involves the development and preparation of semisolid, emulsion-based dosage forms intended for external application to the skin, mucous membranes, or other surfaces to deliver active pharmaceutical ingredients (APIs) for local therapeutic effects or systemic absorption.^[1] These formulations typically consist of an oil-in-water (o/w) or water-in-oil (w/o) emulsion, where the dispersed phase is stabilized by emulsifiers, allowing for controlled drug release, enhanced skin penetration, and improved patient compliance due to their non-greasy texture and ease of spreadability.^[2] Creams are distinguished from ointments by their higher water content (often 50-80%), which imparts a smoother consistency and better cosmetic elegance, making them suitable for conditions like dermatitis, infections, or pain relief.^[1] The primary components of topical creams include APIs such as analgesics (e.g., lidocaine), anti-inflammatories (e.g., hydrocortisone), or antimicrobials, dispersed within a base comprising aqueous and oleaginous phases.^[1] Excipients play crucial roles: emollients like white petrolatum provide occlusion and hydration; emulsifiers such as cetyl alcohol stabilize the emulsion; humectants like polyethylene glycol 400 retain moisture; and preservatives like methylparaben prevent microbial contamination.^[3] The choice of base—such as hydrophilic (e.g., vanishing cream) or lipophilic (e.g., lanolin-based)—influences drug solubility, stability, and bioavailability, with formulations often requiring pH adjustment (typically 4.5-6.5) to match skin physiology and minimize irritation.^[2] Formulation processes employ techniques like high-shear mixing or homogenization to incorporate APIs into pre-mixed bases (e.g., PLO gel or Aquaphor), ensuring uniform distribution and avoiding phase separation.^[1] Quality-by-Design (QbD) principles guide development, focusing on critical quality attributes like viscosity, rheological properties, and in vitro drug release using Franz diffusion cells to predict skin permeation.^[2] Challenges include low drug permeability through the stratum corneum (often <1% for most APIs), potential interactions between excipients and drugs, and variability in manufacturing that can affect bioequivalence.^[1] Regulatory evaluation emphasizes stability testing, microbial limits, and performance metrics, though the absence of standardized reference products for compounded creams complicates approval and generic equivalence.^[1] Advances in penetration enhancers and novel emulsifiers continue to refine formulations for targeted delivery, enhancing efficacy in dermatological and transdermal applications.^[2]

Definition and Properties

Definition

A topical cream formulation is a semisolid dosage form designed for external application to the skin, consisting of an emulsion that combines aqueous and oily phases to deliver active pharmaceutical ingredients (APIs). These formulations are classified as either oil-in-water (O/W) or water-in-oil (W/O) emulsions, providing a versatile vehicle for topical drug delivery.^[4]^[5] The basic composition includes an API dispersed or dissolved within a base that typically incorporates 50-80% water or aqueous components, along with less than 50% hydrocarbons, waxes, or polyethylene glycols to achieve the desired consistency and stability. This structure allows for the incorporation of excipients such as emulsifiers, preservatives, and humectants to ensure homogeneity and efficacy.^[6]^[7] Topical cream formulations evolved from early emulsions developed in the 19th century for pharmaceutical and cosmetic applications, building on ancient practices of mixing oils and waters for skin treatments dating back to Mesopotamian records around 3000-3500 B.C.^[8]^[9] Their advantages include easy spreadability across the skin surface, a non-greasy feel particularly in O/W types that can be readily washed off, and the ability to accommodate both hydrophilic and lipophilic drugs for targeted therapeutic effects.^[10]^[5]

Physical and Chemical Properties

Topical creams exhibit key physical properties that ensure their functionality, such as viscosity, which typically ranges from 5,000 to 50,000 centipoise (cP) to provide optimal spreadability and ease of application on the skin. This shear-thinning behavior allows the cream to remain thick at rest for stability but flow easily under pressure during rubbing. Homogeneity is another critical attribute, assessed through visual inspection and content uniformity tests where relative standard deviation (RSD) is maintained below 5% to confirm even distribution of components without phase separation.^[11] The pH of topical creams is generally maintained between 4.5 and 6.5 to align with the skin's natural acidic mantle (pH ~5) and minimize irritation, as values outside this range can disrupt the skin's natural acidic mantle.^[12] Emulsion stability is essential for long-term integrity, evaluated via centrifugation, freeze-thaw cycles, and microscopy to detect creaming, coalescence, or flocculation; stable formulations show low instability indices (e.g., 0.03–0.28) and minimal sedimentation rates.^[12] Chemical stability is influenced by factors like the hydrophilic-lipophilic balance (HLB) of emulsifiers, with HLB values of 8–18 preferred for oil-in-water (O/W) emulsions to promote proper phase dispersion and prevent degradation.^[13] Topical creams are formulated as either O/W or water-in-oil (W/O) emulsions, each with distinct properties suited to specific skin conditions. O/W creams are non-occlusive, water-washable, and cosmetically elegant, making them ideal for moist or weeping lesions where easy removal and hydration without greasiness are desired.^[14] In contrast, W/O creams are occlusive and protective, forming a barrier that retains moisture and shields dry, chapped, or inflamed skin, though they are greasier and less washable.^[15] Selection criteria prioritize the emulsion type based on the targeted skin condition to optimize therapeutic efficacy and patient comfort. Sensory attributes significantly impact patient compliance, with appearance (e.g., uniform, opaque white consistency), odor (mild or fragrance-free to avoid sensitization), and texture (smooth, non-sticky spreadability) directly influencing adherence to treatment regimens.^[16] These qualities are evaluated through rheological measurements and panel testing to ensure the cream feels non-greasy post-application and absorbs quickly, thereby enhancing user satisfaction and consistent use.^[11]

Skin Anatomy for Topical Delivery

Stratum Corneum

The stratum corneum (SC) is the outermost layer of the epidermis, functioning as the primary barrier to topical drug delivery in cream formulations. It comprises anucleate corneocytes—dead, flattened keratinocytes filled with keratin filaments and cross-linked by disulfide bonds—arranged in 10 to 20 layers, resulting in a typical thickness of 10–20 μm that varies by body site, such as being thicker on the palms (up to ~200 μm) and thinner on the eyelids (around 15 μm).^[17]^[18] These corneocytes are embedded in an intercellular lipid matrix composed primarily of ceramides, cholesterol, and free fatty acids in an approximately equimolar ratio, forming a highly ordered, multilamellar structure.^[19] This organization is classically described by the "brick-and-mortar" model, where corneocytes act as the impermeable bricks and the lipids serve as the hydrophobic mortar, creating a tortuous pathway for permeants.^[20] The SC's lipid matrix establishes a hydrophobic barrier that minimizes transepidermal water loss (TEWL) to prevent dehydration and restricts the ingress of exogenous substances, including active pharmaceutical ingredients from topical creams.^[21] In the context of cream application, lipophilic phases in the formulation—such as oils or emollients—promote partitioning of drug molecules into the SC lipids, governed by the partition coefficient between the vehicle and the skin's intercellular domain, which favors lipophilic actives for initial uptake.^[22] This partitioning is crucial for passive diffusion, as the drug must dissolve in and traverse the lipid bilayers via intercellular routes. To enhance penetration, permeation enhancers (e.g., alcohols or fatty acids) are often included in creams to disrupt the tight lipid packing within the SC, fluidizing the lamellae and increasing intercellular space without permanent damage to the barrier.^[23] Additionally, hydration from humectants (like glycerin) or occlusive components in cream vehicles swells the corneocytes, loosens desmosomal connections, and elevates water content in the SC, thereby boosting diffusivity and overall permeability for both hydrophilic and lipophilic drugs.^[24] Successful navigation through this layer enables subsequent diffusion into deeper skin strata, such as the viable epidermis.^[25]

Viable Epidermis

The viable epidermis, situated beneath the stratum corneum, comprises the stratum granulosum, stratum spinosum, and stratum basale, forming a multilayered structure approximately 50–150 μm thick that varies by body site. This layer is predominantly composed of keratinocytes, which originate in the basal layer and undergo progressive differentiation as they ascend, involving keratin synthesis, organelle degradation, and eventual formation of keratohyalin granules in the granular layer.^[26]^[27]^[28] In topical cream formulations, the viable epidermis facilitates drug absorption primarily through intercellular diffusion pathways, where hydrophilic active pharmaceutical ingredients partition into and traverse the aqueous extracellular spaces between keratinocytes. Lacking blood vessels, this avascular region relies on diffusive nutrient supply from the underlying dermis, which similarly supports drug distribution without immediate vascular clearance.^[29]^[30]^[31] Drug molecules penetrating the outermost stratum corneum barrier can reside and accumulate within the viable epidermal layers, promoting localized therapeutic effects such as anti-inflammatory or antimicrobial action while minimizing systemic exposure. Metabolic processes in these living cells, including enzymatic degradation by epidermal esterases, proteases, and cytochrome P-450 isoforms, may alter the bioavailability of susceptible APIs, necessitating formulation strategies to enhance stability.^[32]^[33]^[34]

Dermis

The dermis, located beneath the viable epidermis, is composed of dense irregular connective tissue primarily produced by fibroblasts, which synthesize collagen and elastin fibers that provide structural support, tensile strength, and elasticity to the skin.^[35] This layer typically measures 1 to 4 mm in thickness, with variations depending on the body site—thinner on the eyelids and thicker on the back—and it incorporates an extensive network of blood vessels, nerves, and lymphatic vessels that supply nutrients, sensory functions, and immune surveillance to the skin.^[36] Unlike the avascular epidermis, the dermis's vascular and connective components enable active interactions essential for tissue repair and drug distribution.^[37] In topical cream formulations, the dermis functions as a critical site for localized therapeutic action, where anti-inflammatory drugs such as corticosteroids exert effects on dermal fibroblasts, immune cells, and vascular elements to reduce inflammation and pain without requiring deep penetration.^[38] Its rich vascular network supports targeted drug distribution within the tissue but can permit limited systemic absorption if the overlying epidermal barrier is breached, such as in cases of compromised skin integrity.^[39] Penetration to the dermis occurs primarily through transdermal routes, including the transappendageal pathway via hair follicles and sebaceous glands or the intercellular route across lipid bilayers of the stratum corneum, allowing lipophilic actives from creams to reach dermal targets efficiently.^[31] Clinically, the dermis is a primary target for conditions involving dermal inflammation, such as eczema (atopic dermatitis), where topical corticosteroids penetrate to modulate immune responses in dermal cells, alleviating symptoms like redness and itching with minimal systemic exposure when applied to intact skin.^[40] This localized delivery minimizes side effects compared to oral administration, highlighting the dermis's role in effective topical pharmacotherapy for inflammatory dermatoses.^[38]

Hypodermis

The hypodermis, also known as the subcutaneous layer, is the deepest layer of the skin, consisting primarily of adipose tissue interspersed with fat cells (adipocytes) and loose areolar connective tissue, along with blood vessels and nerves that provide vascular support and anchorage to underlying structures such as muscles and bones.^[41] This layer functions mainly as an energy storage depot and a protective cushion, with its composition enabling flexibility and metabolic roles beyond mere padding.^[42] The thickness of the hypodermis varies significantly across body regions and individuals, typically ranging from a few millimeters to several centimeters, and is notably thicker in areas like the abdomen (around 14 mm) compared to the limbs (around 10-11 mm) on average in adults.^[43] This variability influences overall skin resilience but plays a limited role in the direct penetration of topical creams, as most formulations are designed to target superficial layers, with drugs rarely reaching the hypodermis due to the formidable barriers posed by the stratum corneum and viable epidermis.^[31] However, if systemic absorption occurs—particularly for lipophilic drugs—the hypodermis can serve as a temporary reservoir, where these compounds partition into the adipose matrix, potentially prolonging their release and distribution.^[44] In the context of topical cream application, the hypodermis contributes to skin occlusion and insulation by maintaining thermal stability and moisture retention beneath applied formulations, which can indirectly enhance local drug retention without targeting the layer itself.^[42] It is rarely the intended site for drug action in topical therapies, yet its properties affect overall pharmacokinetics, especially in obese individuals where increased hypodermal thickness expands the adipose reservoir, potentially altering drug clearance and bioavailability for lipophilic agents that achieve deeper penetration. The boundary between the dermis and hypodermis is marked by a transition to looser connective tissue, which facilitates passive diffusion of deeply penetrating drugs from the denser dermal matrix into the subcutaneous space if vascular access is achieved.^[45]

Pharmacology of Topical Application

Mechanisms of Penetration

The penetration of drugs from topical creams into the skin occurs through distinct biophysical pathways, primarily governed by the structure of the stratum corneum, the outermost skin barrier. The main routes include the intercellular pathway, where molecules diffuse through the lipid matrix between corneocytes; the transcellular pathway, involving direct passage across corneocytes and their surrounding lipid lamellae; and the transappendageal pathway, which utilizes skin appendages such as hair follicles and sweat glands.^[46]^[47]^[48] These pathways are driven by passive diffusion processes, primarily dictated by the concentration gradient across the skin and the drug's partition coefficient, often quantified by log P, which measures lipophilicity and influences partitioning from the vehicle into the stratum corneum lipids. The flux of drug molecules, J, follows Fick's first law of diffusion adapted for skin permeation:

J = -D \frac{dc}{dx}

where J represents the steady-state flux, D is the diffusion coefficient through the skin, and dc/dx is the concentration gradient across the barrier.^[49]^[50] To enhance penetration, formulations incorporate chemical enhancers, such as alcohols (e.g., ethanol) that disrupt stratum corneum lipids by fluidizing the intercellular matrix, and physical enhancers, including occlusion provided by the cream itself, which increases skin hydration and thereby reduces barrier resistance.^[23]^[51]^[52] For most topical drugs, the stratum corneum diffusion represents the rate-limiting step, as it poses the primary resistance to molecular transport due to its compact, lipid-rich structure.^[53]^[54]^[55]

Routes of Drug Administration

The primary route of drug administration for topical creams is percutaneous, also known as transdermal, which involves applying the formulation directly to intact skin to achieve either local therapeutic effects at the application site or systemic absorption into the bloodstream.^[56] This route leverages the skin as a barrier and delivery portal, allowing drugs to penetrate the stratum corneum for localized treatment of conditions such as dermatitis or eczema, while certain formulations enable sustained systemic delivery, bypassing first-pass hepatic metabolism.^[56] For instance, transdermal creams can maintain stable plasma levels of medications like analgesics or hormones over extended periods.^[56] Application techniques play a crucial role in optimizing drug delivery through this route. Rubbing or massaging the cream into the skin increases the surface area of contact and enhances local blood supply, thereby promoting penetration and systemic absorption; this method also induces a mild exfoliative effect that facilitates drug entry.^[57] Occlusion, achieved by covering the applied area with impermeable dressings such as plastic wrap, vinyl gloves, or hydrocolloid materials, further boosts absorption by elevating skin hydration and temperature, potentially increasing penetration by 10 to 100 times compared to non-occluded application.^[57] These techniques exploit underlying penetration mechanisms, such as diffusion across skin layers, to improve efficacy, though occlusion should be used cautiously to avoid accelerated adverse effects or infection, particularly on broken skin where microbial entry risk heightens.^[57] While the focus remains on intact skin, alternative administration sites include mucous membranes, such as in rectal creams designed for local anti-inflammatory action in conditions like hemorrhoids.^[58] Rectal application benefits from the mucosa's thinner epithelial layer and richer vascular supply, enabling faster absorption than skin without the keratinized barrier, though considerations include limited fluid volume (1-3 mL) and potential leakage reducing retention time.^[58] On broken skin, such as wounds or abraded areas, administration requires extra vigilance to prevent irritation or systemic overload due to compromised barrier function.^[57] Topical creams are typically formulated for non-occlusive delivery, distinguishing them from more impermeable ointments or gels that form a tighter barrier on the skin.^[59] As oil-in-water emulsions, creams provide moisturizing and cooling effects suitable for exudative or inflamed skin, vanishing upon rubbing without trapping excessive moisture, which supports their use on cosmetically sensitive areas like the face.^[5] In contrast, occlusive variants or adjunct dressings can be employed with creams to enhance delivery when non-occlusive application proves insufficient, balancing efficacy with patient comfort.^[59]

Factors Influencing Absorption

The absorption of drugs from topical creams into the skin is modulated by several key variables, primarily categorized into drug properties, formulation characteristics, skin conditions, and environmental influences. These factors determine the rate and extent of percutaneous penetration, influencing therapeutic efficacy and potential systemic exposure. Understanding these modulators is essential for optimizing cream formulations to achieve targeted delivery while minimizing variability. Drug physicochemical properties play a pivotal role in absorption efficiency. Molecules with a low molecular weight, ideally below 500 Da, exhibit enhanced skin permeation due to easier diffusion through the intercellular lipid pathways of the stratum corneum. Solubility is another critical attribute, where a balanced lipophilicity—characterized by a log P value between 1 and 3—facilitates partitioning into the lipophilic skin barrier while allowing subsequent release into aqueous layers; drugs outside this range often show reduced bioavailability. The ionization state further governs penetration, with non-ionized forms preferred as they are more lipophilic and compatible with the stratum corneum's lipid matrix; adjusting formulation pH to favor the unionized species can significantly boost absorption. Formulation factors directly impact the drug's thermodynamic activity and release profile at the skin interface. The type of vehicle in the cream emulsion is particularly influential: oil-in-water (O/W) systems enhance the release of hydrophilic drugs by providing an aqueous environment that promotes partitioning into the skin, whereas water-in-oil (W/O) vehicles favor lipophilic compounds but may limit deeper penetration. Concentration gradients drive passive diffusion according to Fick's laws, with higher drug concentrations in saturated solutions creating steeper gradients and thus accelerating absorption rates; supersaturation techniques can further amplify this effect without altering vehicle composition. Skin-related variables alter the barrier function, introducing inter-individual and site-specific differences in absorption. Hydration levels of the stratum corneum, optimally at 20-50% water content, swell corneocytes and disrupt lipid packing, thereby reducing resistance to drug influx and enhancing permeability. Age influences absorption through structural changes: in the elderly, thinner skin and reduced lipid content lead to increased permeability, potentially elevating systemic risks for potent topicals. Disease states, such as psoriasis, compromise the skin barrier by disrupting keratinocyte cohesion and lipid organization, resulting in up to 10-fold higher absorption compared to healthy skin. Environmental conditions modulate skin physiology and indirectly affect drug delivery from creams. Elevated temperatures (e.g., above 32°C) fluidize stratum corneum lipids, increasing molecular mobility and permeation rates by up to 2-3 times per 10°C rise. Humidity influences skin hydration; high relative humidity (>70%) promotes corneocyte swelling and barrier weakening, while low humidity (<30%) tightens the lipid matrix, impeding absorption and emphasizing the need for moisturizing excipients in dry climates.

Formulation Components

Active Pharmaceutical Ingredients

Active pharmaceutical ingredients (APIs) serve as the primary therapeutic components in topical creams, delivering targeted pharmacological effects to treat localized skin conditions or achieve systemic absorption through the skin. These agents exert local actions by interacting with skin structures or regional tissues, or systemic effects via transdermal delivery into the bloodstream. Typical concentrations of APIs in topical creams range from 0.1% to 10% w/w, determined by factors such as drug potency, application area, and intended therapeutic dose to ensure efficacy while minimizing side effects.^[6] Selection of APIs for topical cream formulations prioritizes compounds that demonstrate chemical and physical stability within the emulsion matrix to prevent degradation during storage or application. Compatibility with the skin's natural pH of approximately 4.5–5.5 is essential to avoid irritation and maintain formulation integrity. Additionally, APIs are chosen based on their penetration characteristics, with low molecular weight (typically below 500 Da) and appropriate lipophilicity (log P around 1–3) favoring effective diffusion through the stratum corneum for desired local or transdermal action.^[60]^[61]^[62] Representative examples of APIs in topical creams include corticosteroids such as hydrocortisone at 1% w/w, used to reduce inflammation in conditions like eczema by inhibiting inflammatory mediators. Antimicrobials like clotrimazole at 1% w/w target fungal infections by disrupting ergosterol synthesis in cell membranes, effective against dermatophytes and yeasts. Analgesics such as lidocaine at 4–5% w/w provide pain relief by blocking sodium channels in nerve membranes, commonly applied for localized neuropathic pain.^[63]^[64]^[65] A key challenge in incorporating APIs into topical creams is their poor aqueous solubility, which can limit uniform dispersion and bioavailability. This is often addressed through micronization, reducing particle size to 1–10 μm to increase surface area and dissolution rate without altering equilibrium solubility. Alternatively, complexation with cyclodextrins forms inclusion complexes that enhance solubility and stability, improving release profiles in the formulation.^[66]

Oily Compounds

Oily compounds form the essential lipid component of the oil phase in topical cream emulsions, providing a hydrophobic matrix that supports the overall formulation structure. These compounds are broadly categorized into hydrocarbons, such as petrolatum and mineral oil, which are derived from petroleum and offer high occlusivity due to their non-volatile nature; vegetable-derived oils, exemplified by lanolin, a wool wax alcohol that mimics skin lipids; and synthetic esters like isopropyl myristate, which are engineered for enhanced skin compatibility and penetration properties. Hydrocarbons like petrolatum consist primarily of long-chain alkanes and cycloalkanes, making them inert and stable, while lanolin contains esters of sterols and fatty alcohols that contribute to a semi-solid consistency in creams.^[67]^[68]^[69] The primary functions of oily compounds in topical creams include occlusion, emolliency, and serving as solvents for lipophilic active pharmaceutical ingredients (APIs). Occlusion occurs when these oils form a protective barrier on the skin surface, reducing transepidermal water loss (TEWL) by up to 99% in the case of petrolatum, thereby enhancing skin hydration without penetrating deeply. Emolliency involves softening and smoothing the skin by filling intercellular spaces with lipid droplets, improving texture and reducing roughness, as seen with mineral oil and lanolin applications. As solvents, oily compounds dissolve lipophilic APIs to ensure uniform distribution, though detailed solubility profiles are addressed in active ingredient sections. Typically, the oily phase constitutes 10-30% w/w of the total formulation to balance efficacy and sensory attributes.^[70]^[67]^[71] Selection of oily compounds is guided by the hydrophilic-lipophilic balance (HLB) required for emulsion stability and the comedogenic potential to suit specific skin types. Oils are chosen based on their required HLB value—typically 4-6 for water-in-oil (W/O) emulsions—to match with emulsifiers, ensuring proper dispersion and preventing instability; for instance, mineral oil has a required HLB around 10, influencing blend compositions. Comedogenicity assessments prioritize non-comedogenic options like jojoba oil or squalane for acne-prone skin, avoiding high-potential ingredients such as lanolin (rated 0-2 on the comedogenic scale) or isopropyl myristate (rated 3-5), which can clog pores in susceptible individuals. These criteria ensure the formulation is both stable and dermatologically appropriate.^[72]^[73] In W/O emulsions, oily compounds play a critical role in stability by forming the continuous external phase, which encapsulates water droplets and minimizes coalescence or phase separation over time. The viscosity and density of the oil phase, as provided by petrolatum or synthetic esters, resist gravitational separation and maintain droplet integrity, with studies showing that higher oil content correlates with reduced creaming in such systems. This structural contribution is vital for long-term shelf-life in protective creams.^[74]^[75]

Thickeners and Emulsifying Agents

Thickeners play a crucial role in topical cream formulations by increasing the viscosity of the continuous phase, which enhances the overall texture and stability of the emulsion. Common synthetic thickeners include carbomers, such as Carbopol 934 and Carbopol 980, which are cross-linked polyacrylic acid polymers that swell in water to form clear gels. These agents are typically used at concentrations ranging from 0.5% to 1.5% w/w to achieve desired rheological properties without compromising spreadability. For instance, a 1.5% w/w concentration of Carbopol 934 has been shown to provide optimal viscosity (around 2670 cP) and bioadhesive strength in topical gels for sustained drug release. Xanthan gum, a natural polysaccharide derived from bacterial fermentation, serves as another effective thickener, often incorporated at 0.3% to 3% w/w to impart shear-thinning behavior and improve mucoadhesion in emulsions. In combined systems, such as 0.75% Carbopol with 0.3% xanthan gum, these polymers enhance gel strength and control drug permeation in topical applications like ocular formulations. Emulsifying agents, primarily surfactants, are essential for forming and stabilizing the oil-in-water (O/W) or water-in-oil (W/O) emulsions that characterize topical creams, by reducing interfacial tension between immiscible phases. Non-ionic surfactants like polysorbate 80 (Tween 80), with a hydrophilic-lipophilic balance (HLB) value of approximately 15, are widely used for O/W emulsions due to their ability to solubilize hydrophobic active ingredients and promote droplet formation. In contrast, sorbitan monooleate (Span 80), with an HLB of about 4.3, is suited for W/O systems, providing robust stabilization in anhydrous or high-oil-content creams. HLB matching is critical for emulsion stability; blends of surfactants with complementary HLB values (e.g., 10-20 for O/W) ensure optimal packing at the interface, preventing phase separation over time. The primary functions of thickeners and emulsifiers in topical creams include preventing creaming—where oil droplets rise due to density differences—and coalescence, where droplets merge and destabilize the structure. By elevating the continuous phase viscosity, thickeners like xanthan gum slow Brownian motion and gravitational separation of droplets, while emulsifiers form viscoelastic interfacial films that provide steric and electrostatic barriers against aggregation. This synergy ensures uniform distribution of active pharmaceutical ingredients (APIs), maintaining therapeutic efficacy and aesthetic qualities such as smoothness during application. For eco-friendly formulations, natural alternatives like lecithin—a phospholipid from soy or sunflower sources—act as emulsifiers by adsorbing to oil-water interfaces and enhancing emulsion stability in oleogel-based creams. Similarly, beeswax functions as a natural oleogelator and stabilizer, increasing oil phase density to minimize creaming in high-internal-phase emulsions suitable for cream-like textures.

Preservatives and Antioxidants

Preservatives are essential components in topical cream formulations to prevent microbial contamination and proliferation, thereby ensuring product safety and extending shelf life.^[76] Common synthetic preservatives include parabens, such as methylparaben and propylparaben, which inhibit the growth of bacteria, yeasts, and molds by disrupting microbial cell membranes.^[77] Phenoxyethanol is another widely used preservative, effective against a broad spectrum of microorganisms at typical concentrations of 0.5% to 1.0%.^[78] The efficacy of these preservatives is evaluated through challenge testing, a standardized microbiological procedure that inoculates the product with high levels of test organisms (e.g., 10^5 to 10^6 CFU/g) and monitors log reductions in microbial counts over 28 days to confirm preservative stability and performance.^[79] Regulatory limits govern preservative use to minimize potential risks, such as skin irritation or endocrine disruption. In the European Union, individual parabens are permitted at a maximum concentration of 0.4%, with a total limit of 0.8% for mixtures, while certain variants like isopropylparaben and isobutylparaben are banned due to concerns over reproductive toxicity.^[77] Phenoxyethanol is authorized up to 1.0% in cosmetics, though its use is restricted in products for children under three years or nappy areas.^[78] These agents not only protect against microbial spoilage but also maintain the integrity of the cream, preventing degradation that could compromise therapeutic efficacy or user safety.^[76] Antioxidants in topical creams safeguard the formulation's oily phases from oxidative rancidity, which can lead to off-odors, color changes, and loss of active ingredient potency.^[80] Butylated hydroxytoluene (BHT), a synthetic phenolic antioxidant, is commonly incorporated at concentrations ranging from 0.0002% to 0.5% to scavenge free radicals and interrupt lipid peroxidation chains in emulsion-based systems.^[81] Tocopherol, a natural form of vitamin E, serves a similar role by donating hydrogen atoms to stabilize peroxyl radicals, particularly in oil-rich components like emollients, and is typically used at levels of 0.1% to 1% for optimal protection without pro-oxidant effects.^[82] These antioxidants extend product stability, ensuring the cream remains effective throughout its shelf life.^[83] Amid growing consumer preference for "clean" labels, natural alternatives to synthetic preservatives and antioxidants are increasingly adopted, though their efficacy varies. Grapefruit seed extract (GSE) is promoted as a broad-spectrum antimicrobial agent derived from citrus seeds, often used at 0.1% to 0.5% to inhibit bacterial and fungal growth in water-based formulations.^[84] However, studies indicate that GSE's preservative activity may partly stem from synthetic additives like benzethonium chloride in commercial products, prompting calls for purified natural variants to meet efficacy standards via challenge testing.^[85] This shift reflects broader market demands for paraben-free and synthetic-free options while balancing regulatory requirements for microbial safety.^[86]

Buffer Agents

Buffer agents in topical cream formulations are essential excipients that maintain the pH within a stable range, typically 5-7, to align with the skin's natural acidic mantle (pH 4.5-5.5) and ensure product compatibility.^[87] This range supports skin barrier function, enzyme activity, and microbial balance while preventing disruption of the epidermal lipid processing.^[88] Common types include citric acid and its salts (e.g., sodium citrate), phosphate buffers (e.g., disodium hydrogen phosphate), and organic bases like triethanolamine, which are selected for their compatibility with semi-solid emulsions and ability to adjust pH without compromising texture.^[89]^[90] These agents perform critical functions, including stabilizing active pharmaceutical ingredients (APIs) by preventing pH-dependent degradation such as hydrolysis, which is particularly relevant for ester-based drugs like hydrocortisone-17α-butyrate.^[91] By maintaining an optimal pH, buffers enhance API solubility and skin penetration, as acidic conditions can influence the ionization state of permeants and facilitate diffusion through the stratum corneum.^[88] Additionally, they minimize skin irritation by avoiding extreme pH shifts that could disrupt the acid mantle or provoke inflammatory responses in sensitive or diseased skin.^[87] The effectiveness of buffer agents relies on their capacity to resist pH changes upon addition of acids or bases, governed by the Henderson-Hasselbalch equation for weak acid/base systems:

\text{pH} = \text{p}K_a + \log_{10} \left( \frac{[\text{A}^-]}{[\text{HA}]} \right)

where \text{p}K_a is the negative logarithm of the acid dissociation constant, [\text{A}^-] is the concentration of the conjugate base, and [\text{HA}] is the concentration of the undissociated acid.^[91] This equation allows formulators to predict and optimize buffer ratios for maximum capacity near the target pH (ideally within ±1 of \text{p}K_a), ensuring stability during storage and application; for instance, citrate buffers (pKa values ~3.1, 4.8, 6.4) are effective around pH 5-7.^[89] Buffer capacity is typically maintained at 0.01-0.1 equivalents per liter to balance efficacy without excessive concentration that could affect viscosity.^[91] In cream formulations, buffer agents interact with emulsifiers to prevent phase separation or instability at extreme pH levels, as seen in optimizations combining citric acid/triethanolamine with surfactants like stearic acid derivatives to achieve stable emulsions at pH 5.^[90] Such interactions ensure the oil-in-water or water-in-oil structure remains intact, supporting uniform API release and prolonged shelf-life without altering rheological properties.^[88]

Manufacturing Processes

Preparation Methods

Topical creams are typically prepared as oil-in-water (o/w) emulsions, where the aqueous phase forms the continuous medium and the oil phase is dispersed within it to achieve a smooth, spreadable consistency suitable for skin application. The standard preparation involves a two-phase blending process, beginning with the separate formulation of the aqueous and oil phases to ensure proper dissolution and dispersion of components before emulsification. This method relies on emulsifying agents to stabilize the mixture and prevent phase separation.^[11] In the aqueous phase preparation, water-soluble ingredients such as humectants, thickeners, and emulsifiers are dispersed into purified water, often requiring heating to 70–80°C to facilitate hydration and solubility. Similarly, the oil phase is assembled by melting lipophilic components like waxes, emollients, and oil-soluble emulsifiers at 75–80°C until a homogeneous liquid forms. These phases are then combined while the oil phase is slowly added to the aqueous phase under continuous stirring to initiate emulsification. High-shear mixing or homogenization follows immediately, typically at speeds of 5000 RPM for 5–10 minutes, to reduce droplet size and create a stable emulsion with uniform microstructure. The mixture is then cooled to room temperature with gentle agitation to avoid breaking the emulsion.^[92]^[93] Fusion methods involve melting the base components, such as by heating waxes and oils together before incorporating the aqueous elements, which is particularly useful for anhydrous or w/o emulsions but adaptable to o/w creams for enhanced uniformity. Mechanical blending employs equipment like propeller mixers at low speeds (e.g., 500 RPM) during phase addition, escalating to high-shear devices for refinement. For heat-sensitive active pharmaceutical ingredients (APIs), incorporation occurs post-emulsification and cooling, often below 45°C, using additional mixing to ensure even distribution without degradation.^[93]^[11] Scale-up from laboratory to industrial production transitions from small-scale homogenizers to larger planetary mixers or inline high-shear systems, maintaining critical parameters like temperature and mixing intensity to replicate emulsion quality. Recent advances incorporate the Quality by Design (QbD) approach, which systematically identifies critical process parameters—such as emulsification time, temperature, and shear rate—through risk assessment and design of experiments to optimize formulation robustness and ensure consistent product performance across batches. This methodology, emphasized in 2010s developments, also facilitates continuous manufacturing processes to improve efficiency over traditional batch methods.^[94]^[95]

Quality Control Measures

Quality control measures in topical cream formulation encompass both in-process monitoring and final product testing to ensure consistency, safety, and efficacy. In-process controls focus on maintaining uniformity during mixing and precise temperature regulation during emulsification to prevent phase separation and ensure homogeneous distribution of components. For instance, controlled emulsification systems employ gentle mixing at optimized shear rates to achieve stable formulations, while temperature monitoring—typically between 40°C and 70°C depending on the oil phase—avoids degradation or incomplete emulsification. These steps are critical as deviations in mixing speed or temperature can lead to inconsistent droplet sizes and reduced batch reproducibility.^[96]^[97]^[98] Final product testing includes assays for content uniformity of the active pharmaceutical ingredient (API), commonly performed using high-performance liquid chromatography (HPLC) to quantify drug concentration across multiple samples. This ensures the API is evenly distributed, with acceptance criteria typically requiring relative standard deviation below 5-10% as per pharmacopeial guidelines. Microbial limits testing adheres to USP <61> for nonsterile products, enumerating total aerobic microbial count (TAMC) and total yeast and mold count (TYMC), with limits of TAMC not exceeding 10³ CFU/g and TYMC not exceeding 10² CFU/g for nonsterile topical creams, as per USP <1111>, to mitigate contamination risks.^[11]^[99]^[100]^[101] Specifications for topical creams are governed by compendial standards such as those in the United States Pharmacopeia (USP) and European Pharmacopoeia (EP), which define acceptable ranges for parameters like viscosity (e.g., 5,000-50,000 cP for semi-solid creams) and pH (typically 4.5-7.5 for skin compatibility). These standards ensure the cream's physical stability and sensory attributes, with viscosity measured using rotational viscometers to confirm spreadability and adherence to formulation design.^[102]^[103] Compliance with Good Manufacturing Practices (GMP) requires comprehensive documentation and process validation to achieve batch-to-batch reproducibility, including detailed batch records, in-process sampling protocols, and statistical analysis of critical quality attributes. Under 21 CFR Part 211, manufacturers must establish written procedures for in-process controls that verify uniformity and integrity, with validation studies demonstrating consistent performance across at least three consecutive batches. This framework, aligned with FDA and EMA guidelines, minimizes variability and supports regulatory approval.^[104]^[105]^[106]

Evaluation and Stability

Rheological and Performance Testing

Rheological testing evaluates the flow and deformation properties of topical creams, which are essential for ensuring ease of application, uniform drug distribution, and stability during storage and use. Viscosity flow curves are typically generated using a rotational rheometer with cone-and-plate geometry, applying shear rates from 10 to 900 s⁻¹ to determine parameters such as zero-shear viscosity (η₀), infinite-shear viscosity (η∞), and yield point (τ₀). These measurements reveal the pseudoplastic behavior common in creams, where viscosity decreases with increasing shear, facilitating spreadability on the skin. Thixotropy, the time-dependent recovery of structure after shear, is assessed via hysteresis loop areas during shear rate ramps (e.g., 0.1 to 300 s⁻¹), indicating the formulation's ability to reform its structure post-application for sustained contact with the skin. Brookfield viscometers, often with a spindle at low rpm (e.g., 1 rpm at 20°C), provide complementary viscosity data for quality control, correlating well with advanced rheometry for routine assessments.^[107] Performance testing focuses on the cream's ability to release and deliver the active ingredient effectively. In vitro release studies employ Franz diffusion cells, vertical setups per USP <1724>, where the cream is applied to a synthetic membrane (0.45 μm pore size) at 32°C, with receptor fluid sampled over 4-6 hours to quantify cumulative drug release. This method supports bioequivalence demonstrations by comparing release rates between test and reference products, ensuring linearity (r² ≥ 0.97) and precision (%CV ≤ 15%). Spreadability is quantified using the parallel-plate method, where a fixed sample mass (e.g., 1 g) is placed between glass plates (e.g., 20 × 20 cm) under a weighted upper plate (e.g., 125 g), and the spread diameter is measured after 1 minute; spreadability (S) is calculated as S = (m × l) / (2 × t), with m as weight, l as length, and t as time, promoting uniform dosing and patient compliance.^[108]^[107] Skin permeation assessments determine the distribution of actives within skin layers. Tape-stripping involves applying the cream to excised or in vivo skin, followed by sequential removal of stratum corneum layers using adhesive tapes under consistent pressure, with drug content analyzed via HPLC to profile penetration depth and amount per layer. This minimally invasive technique, aligned with OECD guidelines, quantifies superficial retention and permeation, aiding formulation optimization for targeted delivery. Confocal Raman microscopy (CRM) visualizes non-invasive distribution by scanning skin cross-sections (e.g., 2 μm steps) post-application (15-20 mg/cm² for 4-24 hours), normalizing spectra to skin peaks (e.g., amide I at 1644 cm⁻¹) to map excipient and active intensities versus depth, revealing enhanced penetration kinetics in creams over time.^[109]^[110] For generic topical creams, particularly corticosteroids, bioequivalence is established using skin blanching assays, which measure the pharmacodynamic vasoconstrictor response. The FDA-recommended vasoconstrictor assay applies test and reference products to forearm sites for varying durations (e.g., 3 levels in pivotal studies with ≥40 subjects), assessing blanching via visual scoring or chromametry to compute area under the effect curve (AUEC₀-₂₄hr), with 90% confidence intervals of 80-125% for BE. Pilot studies determine ED₅₀ using the reference standard across 7-9 doses, ensuring method qualification (%CV ≤15%). This approach correlates blanching intensity with clinical efficacy, facilitating generic approvals without full clinical trials.^[111]

Stability and Shelf-Life Considerations

Stability in topical creams refers to the maintenance of product integrity over time, encompassing physical, chemical, and microbiological aspects that prevent degradation and ensure efficacy and safety until the expiration date. Physical stability involves preventing phase separation, creaming, or coalescence of emulsions, which can alter texture and drug release; for instance, improper emulsifier selection may lead to oil droplet aggregation in oil-in-water creams. Chemical stability focuses on protecting active pharmaceutical ingredients (APIs) from degradation pathways like hydrolysis or photolysis, as seen in retinoid-containing creams where exposure to light accelerates isomerization. Microbiological stability guards against contamination by bacteria, fungi, or yeast, critical in water-based formulations that support microbial growth if preservatives are inadequate. Testing for stability follows international guidelines such as ICH Q1A(R2), which recommends both real-time studies at 25°C/60% relative humidity (RH) and accelerated conditions at 40°C/75% RH to simulate long-term storage and stress the formulation, respectively; these protocols allow prediction of shelf-life by monitoring parameters like pH, viscosity, and API content over intervals up to 12 months or more. Shelf-life is quantitatively estimated using the Arrhenius equation, where the rate constant k for degradation is modeled as k = A e^{-E_a / RT}, with A as the pre-exponential factor, E_a the activation energy, R the gas constant, and T the absolute temperature; this enables extrapolation from accelerated data to ambient conditions, though validation is essential for topical semi-solids due to their complex matrices. Real-time data remains the gold standard for confirming the assigned shelf-life, typically 2-3 years for stable creams. Packaging plays a pivotal role in enhancing stability by minimizing exposure to environmental stressors; airless pumps, for example, dispense product without introducing air, thereby reducing oxidation and microbial ingress in sensitive formulations like those with vitamin C derivatives. Light-protective tubes or opaque jars shield photosensitive APIs, such as hydrocortisone, from UV-induced breakdown, extending shelf-life. These choices align with USP <661> standards for container-closure systems in topical products. Recent advances in 2024-2025 have emphasized nano-encapsulation techniques, such as lipid nanoparticles or liposomes, to improve oxidative stability; these carriers encapsulate APIs like curcumin or essential oils, enhancing stability in topical formulations.^[112] This approach not only enhances chemical stability but also supports controlled release, addressing challenges in natural ingredient-based products prone to peroxidation. Preservatives, as discussed in formulation components, further bolster microbiological stability during storage.

Applications

Medical and Therapeutic Uses

Topical creams serve as a key delivery system in dermatology for treating inflammatory, infectious, and comedonal skin disorders, allowing localized application of active pharmaceutical ingredients to minimize systemic exposure.^[40] Their semi-solid base facilitates occlusion and hydration, enhancing drug penetration into the stratum corneum for superficial therapeutic effects.^[113] Common indications encompass dermatitis managed with corticosteroids, bacterial skin infections addressed by antibiotics like mupirocin, and acne vulgaris treated with retinoids.^[40]^[113]^[114] For instance, hydrocortisone 1% cream is a first-line therapy for eczema and atopic dermatitis, exerting local anti-inflammatory action by inhibiting cytokine production and reducing pruritus and erythema, with once-daily application proving as effective as more frequent dosing.^[40] Mupirocin 2% cream targets secondarily infected dermatitis caused by Staphylococcus aureus or Streptococcus pyogenes, inhibiting bacterial protein synthesis to eradicate superficial infections without significant systemic absorption.^[113] Similarly, topical retinoids such as tretinoin normalize follicular keratinization and exhibit anti-inflammatory properties in acne, reducing lesion counts when applied nightly.^[114] Beyond localized action, topical creams enable systemic therapeutic potential through enhanced transdermal absorption, as seen in hormone replacement therapies such as progesterone creams for menopausal symptom relief.^[115] These formulations provide controlled release of hormones like progesterone into the bloodstream, helping alleviate symptoms such as hot flashes and mood changes. Despite these benefits, topical creams have limitations, including poor efficacy against deep-seated infections due to inadequate penetration beyond superficial layers.^[113] Prolonged use of corticosteroid-containing creams also carries a risk of tachyphylaxis, where repeated application leads to diminished therapeutic response through skin tolerance mechanisms, necessitating intermittent dosing to maintain efficacy.^[116]

Cosmetic and Non-Medical Uses

Topical creams serve essential functions in cosmetic and non-medical skincare, primarily through moisturizing and anti-aging mechanisms. Humectants such as glycerin attract and bind water to the skin, enhancing hydration and improving overall skin appearance without the need for therapeutic intervention.^[117] Glycerin, a common ingredient in these formulations, supports skin barrier integrity by increasing moisture retention, making it ideal for daily cosmetic use in products aimed at maintaining supple skin texture.^[118] For anti-aging, ingredients like peptides and hyaluronic acid (HA) are incorporated to promote skin firmness and reduce visible signs of aging; low-molecular-weight HA, for instance, penetrates the skin to boost elasticity and diminish wrinkle depth by up to 6-8% after consistent application.^[119]^[120] Representative examples include day creams formulated with SPF for photoprotection alongside hydration, such as those combining emollients and UV filters to shield skin during daily exposure while delivering a lightweight feel. Night repair creams, often enriched with peptides and botanical extracts, target overnight rejuvenation to smooth fine lines and enhance glow. Market trends in 2025 emphasize a shift toward natural ingredients and biotech actives, with innovations like exosome-based delivery systems gaining traction for their microbiome-supportive and sustainable profiles in cream formulations.^[121] Consumer demand for clean labels—free from synthetic preservatives—drives this evolution, prioritizing efficacy from bio-derived sources.^[122] These creams offer benefits centered on skin barrier repair and non-occlusive hydration, where humectants draw moisture into the stratum corneum to restore lipid balance and reduce transepidermal water loss without forming a heavy film. This approach improves skin tolerability and quality of life by fostering a smooth, resilient surface suitable for cosmetic enhancement. Emollients in these formulations fill intercellular gaps, further aiding repair while aligning with preferences for transparent, eco-friendly products.^[123] An overlap exists with pharmaceutical applications in over-the-counter (OTC) moisturizers, where cosmetic claims for beautification can border drug-like effects on skin structure if they imply disease prevention or functional alteration, as defined by FDA regulations. Such products must comply with both cosmetic labeling for inactive ingredients and drug monographs for active components, blurring lines in formulations like those with barrier-restoring lipids.^[124]^[125]

Comparisons with Other Forms

Differences from Gels

Topical creams and gels differ fundamentally in their composition, with creams formulated as emulsions consisting of an oil-in-water or water-in-oil dispersion, typically containing 20-50% hydrocarbons, waxes, or lipids alongside water and emulsifiers to create a stable semi-solid base.^[126] In contrast, gels are semi-solid systems formed by dispersing gelling agents, such as carbomers or cellulose derivatives, in an aqueous or hydroalcoholic medium without a significant oil phase, resulting in a clear, jelly-like structure that traps liquids in a three-dimensional polymer network.^[126] These compositional variances lead to distinct physical properties and skin interactions. Creams exhibit a viscous, opaque texture that provides emollient and moderately occlusive effects, forming a protective barrier on the skin that reduces transepidermal water loss while allowing some breathability.^[126] Gels, however, are transparent, non-greasy, and quick-drying, often imparting a cooling sensation due to evaporation of their water or alcohol content; they spread easily and leave a thin, non-occlusive film upon application.^[126] Consequently, creams are more hydrating and suitable for prolonged contact, whereas gels minimize residue and are less likely to feel heavy on the skin.^[126] In terms of applications, creams are preferred for conditions involving dry or compromised skin barriers, such as eczema or psoriasis, where their emollient properties help restore moisture and serve as an alternative to more occlusive forms for flexural or genital areas.^[126] Gels, by comparison, are ideal for oily, acne-prone, or hairy skin regions like the face, scalp, or back, as their lightweight nature avoids exacerbating oiliness or clogging follicles, and they facilitate targeted delivery in areas requiring rapid absorption without greasiness.^[126] Regarding advantages and disadvantages, creams excel in delivering lipophilic drugs due to their oil phase, which enhances solubility and sustained release for hydrophobic actives, though they may feel greasy and potentially clog pores in humid environments.^[126] Gels offer superior penetration for hydrophilic drugs through their aqueous matrix and non-occlusive design, promoting faster onset but with drawbacks like reduced moisturization, potential drying effects, and irritation from alcohol components in sensitive skin.^[126] Overall, the choice between them depends on skin type, drug solubility, and therapeutic goals, with creams prioritizing hydration and barrier support while gels emphasize elegance and quick application.^[126]

Differences from Ointments

Topical creams and ointments differ fundamentally in their composition, with creams formulated as biphasic emulsions typically containing approximately equal parts oil and water, often in an oil-in-water or water-in-oil configuration to achieve a semi-solid consistency.^[127] In contrast, ointments are anhydrous greases composed primarily of 70-80% petrolatum or other hydrocarbon bases, lacking significant water content and resulting in a thicker, more uniform oily matrix.^[128] This compositional variance directly influences their physical properties: creams are generally washable and non-greasy, allowing for easier application and removal without residue, making them suitable for daily use on larger areas.^[129] Ointments, however, are highly occlusive and protective, forming a barrier that prevents moisture loss but often feels messy and can stain clothing due to their greasy texture.^[5] These property differences extend to their clinical applications, where creams are preferred for acute or inflamed lesions, such as those with weeping or exudative characteristics, as their lighter base facilitates evaporation and reduces the risk of maceration.^[59] Ointments, by virtue of their occlusive nature, are better suited for chronic dry conditions like psoriasis, where they help maintain skin hydration and protect against environmental irritants in thickened, scaly plaques.^[130] Regarding drug absorption, ointments enhance penetration of active ingredients through occlusion, which increases hydration and permeability of the stratum corneum, thereby improving efficacy for barrier-compromised skin.^[5] Creams, while absorbing more readily into the skin due to their emulsion structure, offer greater cosmetic appeal with less residue, prioritizing patient compliance in non-occlusive scenarios.^[127]

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The oily phase may constitute not more than about 50% w/w of the total ... w/w, and about 10-30% w/w. The functions of the oily phase and/or its ...
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Investigation Utilizing the HLB Concept for the Development of ...
The current study aims to utilize the concept of the hydrophilic–lipophilic balance (HLB) value of ingredients for the development of a stable emulsion-based ...
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Comedogenicity in cosmeceuticals: A review of clinical relevance ...
Sep 12, 2025 · This review emphasizes the need for standardized, human-based testing on final product formulations to determine true comedogenic potential. It ...
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(PDF) The Role of Oil Phase in the Stability and Physicochemical ...
Jun 24, 2019 · This study revealed that using oils with lower viscosity and higher density led to the higher stability of the emulsion samples. ResearchGate ...<|control11|><|separator|>
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Emulsions and creams - Clinical Gate
Feb 8, 2015 · The selection of the oil phase will depend on many factors including the desired physical properties of the emulsion, the miscibility of the oil ...
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Cosmetics Preservation: A Review on Present Strategies - PMC
Challenge Test. The challenge test is used during product development to determine the efficacy and stability of the preservative system over time. The test ...
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[PDF] Amended Safety Assessment of Parabens as Used in Cosmetics
Aug 29, 2018 · The Panel noted that the European Union (EU) has banned the use of 5 parabens (Isopropylparaben,. Isobutylparaben, Phenylparaben, Benzylparaben, ...
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[PDF] 29 of the Cosmetics Regulation (EC) n. 122
Phenoxyethanol is regulated in Annex V, authorized as a preservative at 1.0% max, but concerns exist for children under 3, and not for nappy areas.
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Microbiological Quality Assessment of Skin and Body care ... - NIH
Feb 28, 2024 · The Microbial Challenge test is a procedure to evaluate the preservative efficacy by challenging the product with testing microorganisms to determine the ...
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Antioxidants: a comprehensive review - PMC - PubMed Central
They function as antioxidants and, even at low concentrations, help protect food from oxidative rancidity (Karakaya 2004). The antioxidant potential of phenolic ...
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Final report on the safety assessment of BHT(1) - PubMed
BHT is used in a wide range of cosmetic formulations as an antioxidant at concentrations from 0.0002% to 0.5%. BHT does penetrate the skin.
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[PDF] Safety Assessment of Tocopherols and Tocotrienols as Used in ...
Most of the tocopherols are reported to function in cosmetics as antioxidants or skin conditioning agents; tocotrienols is not reported to function as an ...
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The importance of antioxidants and place in today's scientific and ...
Jul 29, 2019 · These preservative include natural antioxidants such as ascorbic acid and tocopherols, as well as synthetic antioxidants such as propyl gallate ...Missing: topical cream
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Grapefruit Seed Extract as a Natural Derived Antibacterial ... - NIH
Jan 18, 2021 · The antibacterial effect of GSE can be exhibited by benzethonium chloride, a preservative commonly used in commercial GSE [44], but the GSE used ...
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Aspects of the antimicrobial efficacy of grapefruit seed extract and its ...
In only one of the grapefruit seed extracts tested no preservative agent was found. However, with this extract as well as with several self-made extracts from ...
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Deciphering trends in replacing preservatives in cosmetics intended ...
Aug 17, 2024 · The present study aims to investigate the current trends in replacing conventional preservatives with multifunctional ingredients with antimicrobial properties.
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Towards Optimal pH of the Skin and Topical Formulations - MDPI
If the formulation needs a pH adjustment and/or stabilization, frequently used ingredients are lactic and citric acid, sodium acetate, sodium lactate, sodium ...Missing: phosphate triethanolamine
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pH and Buffer Capacity of Topical Formulations - PubMed
The pH is an important physicochemical factor that plays a significant role in various metabolic, molecular and cell-regulating processes.
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Buffers in Pharmaceutical Systems, Preparation, Stability of Buffers
In creams and ointments: A buffer is used to ensure the stability of topical products (which are applied to the skin, such as ointments).
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BUFFER AND EMULSIFIER OPTIMIZATION IN CREAM WITH ITS ...
Dec 1, 2015 · This study aimed to determine the optimal formulation from buffer combination between citric acid, ascorbat acid, and triethanolamine that produce pH 5.Missing: phosphate 5-7
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(PDF) Buffers and pH Adjusting Agents - ResearchGate
Jul 14, 2017 · conjugate base) or a weak base and its salt (i.e.,its conjugate acid). a. The Henderson-Hasselbalch equation, also known as the buffer equation, ...<|control11|><|separator|>
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[PDF] Semi-Solid Topical Formulary | Pharma Excipients
Phase A (Oil) – Prepare phase A by adding each excipient (emollient, consistency factor, and emulsifier) into an appropriately sized beaker. Heat the mixture to.
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Production of Pharmaceutical Creams and Ointments - US - Silverson
Emulsifiers, thickeners and stabilizers are dispersed into water in a separate vessel. Heating may be required to accelerate hydration. Forming the Emulsion.
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Generic Development of Topical Dermatologic Products, Part II
QbD begins with defining a quality target product profile (QTPP) as well as critical quality attributes (CQAs). This is followed by risk identification of the ...
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Solving Dosage Uniformity and Stability Challenges ... - MXD Process
Our Solution: Controlled emulsification systems provide stable formulations while temperature-controlled processing preserves API integrity. Gentle mixing ...
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Thermoregulation during the production phases of cosmetic creams
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A Troubleshooting Guide for Topical Drug Manufacturing
If a formulation is transferred to a contract manufacturer, changes in mixing speeds, temperature controls, and order of ingredient addition may be needed.
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Q6A Specifications: Test Procedures and Acceptance Criteria ... - FDA
Apr 14, 2020 · both assay of the new drug substance and quantitation of impurities. Results of content uniformity testing for new drug products can be used.
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[PDF] 61 MICROBIOLOGICAL EXAMINATION OF NONSTERILE ...
The volume of the suspension of the inoculum should not exceed 1% of the volume of diluted product.
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[PDF] 〈3〉 Topical and Transdermal Drug Products 1 - USP-NF
Nov 1, 2013 · INTRODUCTION. Assay: A specific and stability-indicating test should be used to determine the strength (content) of the drug prod-.
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Understanding the Role of USP and EP Standards in Pharma QC
Oct 22, 2025 · USP and EP are compendial resources that define quality benchmarks for pharmaceutical substances, dosage forms, excipients, and laboratory test methods.
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21 CFR Part 211 -- Current Good Manufacturing Practice for ... - eCFR
(a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and ...Missing: cream | Show results with:cream
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[PDF] Process Validation: General Principles and Practices | FDA
CGMP documents for commercial manufacturing (i.e., the initial commercial master batch production and control record (§ 211.186) and supporting procedures) ...Missing: cream | Show results with:cream
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[PDF] Guideline on process validation for finished products
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https://www.fda.gov/files/drugs/published/Process-Validation--General-Principles-and-Practices.pdf
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[PDF] In Vitro Release Test Studies for Topical Drug Products Submitted in ...
A reference standard, which is selected by FDA, is the specific drug product that the ANDA a pplicant must use in conducting a ny in vivo bioequivalence testing ...<|separator|>
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https://doi.org/10.3390/pharmaceutics15071810
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https://www.fda.gov/media/162476/download
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[PDF] Topical Dermatologic Corticosteroids – In Vivo Bioequivalence - FDA
Sep 13, 2023 · approach to assess the bioequivalence (BE) of topical dermatologic corticosteroids. ▫ Using skin blanching to assess BE of topical ...
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Topical Antibiotic Treatment in Dermatology - PMC - NIH
Jan 17, 2023 · Topical antibiotics play a key role in dermatology and have several uses, including mild-to-moderate acne vulgaris, secondarily infected dermatitis, rosacea, ...
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Acne: Diagnosis and treatment - American Academy of Dermatology
Dermatologists also may recommend a topical retinoid as a maintenance treatment. This type of treatment can keep your skin clear once acne is under control. The ...
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Nicotine (transdermal route) - Side effects & dosage - Mayo Clinic
Feb 1, 2025 · Nicotine skin patches are used to help you stop smoking. Nicotine is absorbed from the patch on the skin and enters the blood stream.
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The effectiveness of the nicotine patch for smoking ... - PubMed
Active patch subjects were more than twice as likely to quit smoking as individuals wearing a placebo patch, and this effect was present at both high and low ...
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Topical corticosteroids in dermatology
Topical corticosteroids are susceptible to develop tachyphylaxis. Tachyphylaxis (acute tolerance) is defined as a rapidly diminishing response to successive ...
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Moisturizers - StatPearls - NCBI Bookshelf - NIH
Feb 12, 2024 · Glycerin is another commonly used humectant and is present in many skincare products. In addition to attracting and binding water, it has ...
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Moisture retention of glycerin solutions with various concentrations
Jun 17, 2022 · The aim of this study was to analyze the moisture-retention capacity of glycerin, a common ingredient in cosmetic products.
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Development and Evaluation of a Novel Anti-Ageing Cream Based ...
Oct 18, 2023 · This study confirmed the skin tolerance and efficacy of the new complex anti-ageing cream incorporating HA, microencapsulated sodium hyaluronate, ectoin, and a ...
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Benefits of topical hyaluronic acid for skin quality and signs of ... - NIH
Oct 21, 2022 · Numerous studies support HA‐based cosmeceuticals as a noninvasive, effective solution for improving skin hydration and rejuvenation.
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5 recent breakthroughs in cosmetic science
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6 Top Beauty Industry Trends (2025 & 2026) - Exploding Topics
Oct 3, 2025 · 1. Continued Emphasis On Natural and Organic Ingredients · 2. Hyper-Personalization with AI and AR · 3. Biotech Innovations with a Focus on ...Missing: actives | Show results with:actives
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The Role of Moisturizers in Addressing Various Kinds of Dermatitis
After rubbing moisturizer in both palms, it should be lightly applied along hair follicles direction. To prevent oil folliculitis from vigorous rubbing, ...
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Sep 11, 2024 · Whether a product is a cosmetic or a drug under the law is determined by a product's intended use. Different laws and regulations apply to each type of product.
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Vehicles for Drug Delivery and Cosmetic Moisturizers - NIH
Topical formulations with a high lipid content, as found in ointments and creams, form a protective occlusive barrier on the skin, protect from harmful ...
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https://www.fda.gov/cosmetics/cosmetics-laws-regulations/it-cosmetic-drug-or-both-or-it-soap
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Ointments contain 80% oil and are better for dry skin, while creams have equal parts oil and water and are good for the face and hands. Ointments lock in ...
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Ointment vs. Cream, Lotion, and Gel: What Makes Them Different?
Oct 21, 2020 · The primary difference between the two lies in the ratio between oil and water. While a cream has equal parts oil and water, ointments contain about 80 percent ...<|control11|><|separator|>
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Psoriasis Medication - Medscape Reference
Topical corticosteroids are the mainstay of treatment for mild and limited psoriasis. They can reduce plaque formation. These agents have anti-inflammatory ...