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Safety and efficacy of drugs with altered physical properties after high temperature exposure(docs.google.com)

1 point by karyan03 1 month ago | flag | hide | 0 comments

Expert Analysis Report on the Safety and Efficacy of a Pharmaceutical Product with Altered Physical Properties After High-Temperature Exposure: A Case Study of Dong-A Pharmaceutical's D-Panthenol Ointment

I. Executive Summary: Final Assessment of a Heat-Exposed Pharmaceutical Product

1.1. Initial Assessment and Core Conclusion

To state the core conclusion of this report unequivocally, the Dong-A Pharmaceutical D-Panthenol Ointment, which liquefied and subsequently re-solidified after exposure to high temperatures, is recommended for immediate disposal. The use of this product is not advised due to the irreversible physical damage to its structure, the high probability of chemical degradation of its active and other ingredients, and the consequent serious risks of diminished efficacy and adverse skin reactions.

1.2. Summary of Key Rationale

This determination is based on three critical factors:

  • Irreversible Structural Collapse: The liquefaction and re-solidification observed by the user signify that the ointment's delicate emulsion structure has been permanently destroyed, a state that cannot be restored by cooling.
  • Compromised Chemical Integrity: The high-temperature environment has likely accelerated the decomposition of the active ingredient, dexpanthenol, and may have induced abnormal chemical reactions among the other excipients that form the ointment's base.
  • Violation of Regulatory and Safety Standards: The storage conditions described are a severe breach of the manufacturer's specified storage requirements (below 25∘C).1 The "change in physical properties" itself, from a regulatory standpoint, means the product's quality can no longer be assured and can be grounds for a product recall.5

1.3. Report Structure

This report will systematically analyze the scientific basis for this recommendation. It will proceed by examining the breakdown of the emulsion system, which constitutes the ointment's physical structure; assessing the chemical stability of each ingredient; providing a comprehensive risk analysis of using the altered product; and finally, offering guidance on safe disposal methods.

II. Physical Transformation: The Disintegration of the Ointment's Emulsion System

This section provides an in-depth explanation of the liquefaction phenomenon observed by the user and the invisible, permanent damage that has occurred.

2.1. The Structure of a Medicated Ointment: More Than a Simple Cream

Dong-A Pharmaceutical's D-Panthenol Ointment is not a simple mixture but a highly engineered emulsion formulation. An emulsion is a system in which two immiscible liquids, such as water (purified water) and oil (shea butter, lanolin, etc.), are dispersed, with one liquid existing as microscopic droplets within the other. This is a thermodynamically unstable system.6 To maintain this unstable structure, emulsifiers such as Glyceryl Stearate SE and Cetostearyl Alcohol are used. This sophisticated structure is key to the product's smooth application, stability, and, most importantly, its ability to effectively deliver the active ingredient, dexpanthenol, to the skin.9 The inclusion of purified water, various oils and butters, and emulsifiers in the ingredient list clearly indicates that this product is a complex emulsion system.

2.2. The Principle of Liquefaction: Dissolution of the Formulation Matrix

The liquefaction of the ointment observed by the user is a direct result of the temperature inside the car, parked under the summer sun, exceeding the melting points of the key ingredients that form the ointment's structural backbone. Even if the external air temperature was 32∘C, the interior of a sealed vehicle exposed to direct sunlight can easily reach temperatures of 50∘C to 70∘C or higher, creating an oven-like environment.11 This temperature is more than sufficient to melt the lipid-based components that maintain the ointment's structure.

  • Shea Butter: Melting point approx. 32−40∘C 12
  • Lanolin: Melting point approx. 38−44∘C 15
  • Cetostearyl Alcohol: Melting point approx. 48−56∘C 18
  • Stearic Acid and Palmitic Acid: These solid fatty acids provide hardness to the formulation, and their melting points would also be exceeded within this temperature range.

The table below summarizes the thermal properties of the ointment's main structural components, demonstrating the clear causal link between high-temperature exposure and physical melting.

Table 1: Thermal Properties of Key Structural Excipients

Ingredient (English)Melting Point (∘C)Role in FormulationReferences
Shea Butter32−40Emollient, Thickener12
Lanolin38−44Emulsifier, Emollient15
Cetostearyl Alcohol48−56Emulsion Stabilizer, Thickener18
Stearic/Palmitic AcidApprox. 55−70Thickener, Emulsifier(General Chemical Data)

2.3. The Illusion of Recovery: Irreversible Emulsion Breakdown

This is the most critical point of this section. The fact that the ointment re-solidified upon cooling in no way means it has returned to its original state. During the heating process, the countless microscopic oil phase and water phase droplets, which were finely dispersed within the melted formulation, moved freely and collided with one another, leading to a phenomenon called coalescence, where smaller droplets merge to form larger ones. This coalescence process is irreversible.20

A simple analogy would be melting an intricate ice sculpture and then refreezing it. The result is merely a solid block of ice; the original delicate form is lost forever. Similarly, while the ointment may have regained a solid form, its original microstructure of uniform dispersion has been completely destroyed. The heat provided the activation energy necessary to overcome the stabilizing barrier created by the emulsifiers, promoting the separation of the thermodynamically unstable emulsion.7 The subsequent cooling process simply "froze" this newly formed, unstable, and non-uniform state in place. The product is now no longer a uniform emulsion but closer to a heterogeneous mixture of large oil globules and water pockets.23

This structural change directly impacts the product's performance. The broken emulsion will have a different texture, may exhibit further separation over time, and, most importantly, has lost its ability to deliver the active ingredient uniformly to the skin. This could result in some areas of the skin receiving no active ingredient at all, while others receive an excessive concentration, thereby increasing the risk of irritation.6

III. Chemical Integrity Analysis: Ingredient-Specific Stability Assessment

This section moves beyond the physical structure to evaluate the potential for chemical degradation of each component.

3.1. The Active Ingredient: The Fate of Dexpanthenol

Dexpanthenol is the alcohol pro-vitamin form of pantothenic acid (Vitamin B5). It must be enzymatically converted to pantothenic acid after absorption into the skin to exert its pharmacological effect 26, making its own chemical stability paramount.

While some sources may mention the high thermal stability of dexpanthenol 28, this is a very general statement and can be misleading under specific conditions. More precise chemical data indicate that dexpanthenol is susceptible to degradation under certain conditions, which are accelerated by heat.

  • Decomposition upon Heating: Chemical databases explicitly state that dexpanthenol decomposes upon heating or distillation.27
  • Risk of Hydrolysis: The primary degradation pathway is hydrolysis, a reaction with water. This reaction is highly pH-sensitive; dexpanthenol is most stable in the pH range of 4-6, and its degradation accelerates rapidly outside this range.29 The ointment in question contains "purified water," meaning the necessary reactant for hydrolysis is present.

It is crucial to note that extreme heat does not merely supply energy for the degradation reaction. Heat can also affect the ionization state of other ingredients in the formulation (e.g., acids, glycols), subtly altering the overall pH of the system. If this pH shifts even slightly outside the optimal 4-6 range, the rate of dexpanthenol hydrolysis can increase dramatically. Therefore, heat acts as both a direct cause and an indirect catalyst for the destruction of the active ingredient.

Table 2: Dexpanthenol (Vitamin B5 Precursor) Stability Profile

Stability FactorEffect on DexpanthenolRelevance to the Current SituationReferences
HeatDecomposes upon heating. Accelerates other degradation reactions.The product was exposed to significant high temperatures (approx. 50−70∘C) for 8 hours.27
Water (Purified Water)Essential for the primary degradation pathway, hydrolysis.The formulation explicitly includes 'purified water'.29
pHUnstable outside the pH 4-6 range, with rapid hydrolysis.High temperatures may have caused a pH shift in the formulation into an unstable range.30
Degradation ProductsPantothenic acid (intended substance) and other inactive fragments.The concentration of effective dexpanthenol has very likely decreased.26

3.2. The Excipient Matrix: Potential for Chain Chemical Reactions

The stability of an ointment must consider the stability of the entire formula. While some ingredients are heat-resistant, others are vulnerable.

  • Stable Ingredient: Dimethicone has excellent thermal stability and is unlikely to have degraded.33
  • Vulnerable Ingredients:
    • Lipids (Shea Butter, Lanolin): Exposure to high temperatures and oxygen (including residual air in the tube) can accelerate the oxidation of fats and oils, leading to rancidity. This can generate irritant compounds and cause an unpleasant odor.36
    • Glycols (Butylene Glycol, Dipropylene Glycol) and Glycerides (Mono- and Diglycerides): While generally stable, some data suggest that components like glycerin can decompose into harmful substances such as acrolein at high temperatures. Although this typically occurs at much higher temperatures, the possibility of trace amounts of degradation from prolonged high-heat exposure cannot be entirely ruled out.37

The greatest unknown risk lies in the interaction of all 15+ ingredients in a high-energy, semi-liquid state.38 The original formulation was validated for stability under conditions below

25∘C. However, at temperatures above 60∘C, unforeseen and unstudied new chemical reactions could occur between the degraded fragments of some molecules and other intact molecules. This product should no longer be considered the validated formula, but rather an unknown new chemical mixture.

IV. Comprehensive Risk Assessment: Efficacy, Safety, and Regulatory Compliance

This section synthesizes the preceding physical and chemical analyses to present clear risk factors.

4.1. Efficacy Degradation: A Dual Failure

The product's ability to perform its therapeutic function has been severely compromised for two main reasons:

  1. Chemical Inactivation: As explained in section 3.1, the concentration of active dexpanthenol has likely decreased due to heat-accelerated hydrolysis.
  2. Physical Delivery Failure: As explained in section 2.3, the destroyed emulsion structure can no longer guarantee the uniform application and effective penetration of even the remaining active ingredient into the skin. Therefore, the product will not work as intended.9

4.2. Dermatological Risk: From Soothing Ointment to Potential Irritant

Using the altered product carries a substantial risk of causing skin irritation, such as redness, itching, stinging, and contact dermatitis.39 This risk stems from multiple sources:

  • Degradation Byproducts: The chemical breakdown of dexpanthenol, fats, glycols, etc., can create new irritant compounds that were not present in the original formulation.
  • Non-uniform Application: The broken emulsion can deliver certain ingredients (e.g., glycols, preservatives) in concentrated 'hot spots' on the skin, irritating the skin barrier and triggering hypersensitivity reactions.
  • Microbial Contamination: While heat alone may not be the primary cause of microbial growth, if the product's preservative system (e.g., 1,2-Pentanediol) was compromised by the heat, it could create an environment where bacteria can proliferate upon subsequent microbial entry.40

Notably, D-Panthenol ointment is primarily used on sensitive or compromised skin. Applying a chemically altered product containing potential irritants to such skin significantly increases the risk of severe adverse effects.

4.3. The Regulatory Perspective: Why a "Change in Physical Properties" is a Critical Flaw

Manufacturers of pharmaceuticals and quasi-drugs must adhere strictly to the storage conditions specified on the product label.1 This is not merely a recommendation but a condition under which the product's safety and stability have been rigorously tested and validated according to regulatory guidelines.45

The South Korean Ministry of Food and Drug Safety (MFDS) considers a change in physical properties (성상 변화) to be a serious quality defect. There have been past cases where products were voluntarily recalled and faced administrative action due to changes in appearance, such as discoloration.5 The liquefaction observed by the user is a clear "change in physical properties." From a quality assurance and regulatory standpoint, this product has already failed and cannot be considered the same as the product that was approved for sale. Continuing to use it is equivalent to using a product that fails to meet quality control standards.

V. Final Conclusion and Actionable Recommendations

5.1. Final Recommendation: Dispose of the Product Immediately

Based on the overwhelming evidence of irreversible physical damage, the potential for chemical degradation of the active ingredient, and the unacceptable risk of skin irritation, the D-Panthenol ointment in question is no longer safe or effective. It must be discarded.

5.2. Summary of Analysis

  • Physical Failure: The emulsion structure has been permanently destroyed.20
  • Chemical Failure: The active ingredient, dexpanthenol, has likely degraded, and unknown harmful byproducts may have formed.27
  • Safety Failure: The risk of skin irritation far outweighs any potential benefit.39
  • Regulatory Compliance Failure: The product has been exposed to conditions outside its validated storage parameters and has undergone a significant physical change.1

5.3. Guidance on Safe Disposal

Do not discard the ointment in household trash or squeeze it down the sink. This can lead to soil and water pollution.48

Correct Disposal Method:
The ointment, in its original tube, should be taken to a designated collection point for waste pharmaceuticals. These collection points are typically located at:

  • Local pharmacies
  • Public health centers
  • Some community service centers (Jumin Centers)

These facilities collect waste pharmaceuticals for disposal via high-temperature incineration (above 850∘C). This process ensures that active chemical ingredients are safely destroyed, preventing harm to the environment.48

5.4. Preventive Best Practices for Medication Storage

All medications, including ointments and creams, should always be stored in a cool, dark, and dry place according to the manufacturer's instructions. In particular, locations with extreme temperature and humidity fluctuations, such as bathrooms or the inside of vehicles, should be avoided.11 This is the most fundamental principle for ensuring that a product remains safe and effective throughout its shelf life.

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  51. 사람 살리는 약이 생태계를 파괴한다고? - 오마이뉴스, 8월 4, 2025에 액세스, https://www.ohmynews.com/NWS_Web/View/at_pg.aspx?CNTN_CD=A0003033226
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